Oncol Lett
. 2020 Jul;20(1):981. doi: 10.3892/ol.2020.11577. Epub 2020 Apr 27.
Relationship Between DLK1 Gene Promoter Region DNA Methylation and Non-Small Cell Lung Cancer Biological Behavior
Zhaokui Zhong, Yongting Ye, Wei Guo, Yi He, Weicai Hu
PMID: 32566029 PMCID: PMC7285830 DOI: 10.3892/ol.2020.11577
Free PMC article
Abstract
[This retracts the article DOI: 10.3892/ol.2017.6019.].

Copyright: © Zhong et al.

Retraction of
Relationship between DLK1 gene promoter region DNA methylation and non-small cell lung cancer biological behavior.
Zhong Z, Ye Y, Guo W, He Y, Hu W.
Oncol Lett. 2017 Jun;13(6):4123-4126. doi: 10.3892/ol.2017.6019. Epub 2017 Apr 10.
PMID: 28588700 Free PMC article. Retracted.
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2
Oncol Lett
. 2020 Jul;20(1):974-980. doi: 10.3892/ol.2020.11612. Epub 2020 May 13.
Expression of ASAP1 and FAK in Gastric Cancer and Its Clinicopathological Significance
Qiong Luo 1, Suyun Zhang 1, Donghuan Zhang 1, Fang Yuan 2, Xiangqi Chen 2, Sheng Yang 1
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PMID: 32566028 PMCID: PMC7285715 DOI: 10.3892/ol.2020.11612
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Abstract
The present study aimed to analyze the expression levels of adenosine diphosphate ribosylation factor guanylate kinase 1 (ASAP1) and focal adhesion kinase (FAK) in gastric cancer (GC) tissues in order to explore their association with clinicopathological features and prognosis. A total of 32 patients with GC were enrolled in the present study. All patients had complete clinical follow-up data and paraffin-embedded normal gastric mucosal tissues. The expression levels of ASAP1 and FAK in these tissues were measured by immunohistochemistry. The associations of ASAP1 and FAK expression with clinicopathological factors and the survival of patients with GC were subsequently analyzed. The expression levels of ASAP1 (59.4%) and FAK (68.8%) in GC tissues were significantly higher than those in normal gastric mucosal tissues (28.1 and 40.6%, P<0.05). The expression levels of ASAP1 and FAK were associated with depth of invasion, lymph node metastasis and pathological stage (P<0.05). ASAP1 expression was positively associated with FAK expression (P<0.001). In addition, ASAP1 and FAK expression levels were negatively associated with disease-free survival time and overall survival time (P<0.05). The 5-year overall survival rate was significantly higher in patients with negative ASAP1 or FAK expression compared with that in patients with positive ASAP1 or FAK expression (P<0.05). In conclusion, ASAP1 and FAK were highly expressed in human GC tissues and may serve a synergistic role in promoting tumorigenesis, progression, invasion and metastasis in patients with GC. ASAP1 and FAK expression in GC were associated with patient's survival. Therefore, ASAP1 and FAK may represent novel molecular markers for the pathophysiology and prognosis of GC.

Keywords: adenosine diphosphate ribosylation factor guanylate kinase 1; focal adhesion kinase; gastric cancer; prognosis.

Copyright © 2020, Spandidos Publications.

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Oncol Lett
. 2020 Jul;20(1):967-973. doi: 10.3892/ol.2020.11592. Epub 2020 May 6.
Promoter Hypermethylation of Cysteine Dioxygenase Type 1 in Patients With Non-Small Cell Lung Cancer
Wei Yin 1, Xiang Wang 1, Yunping Li 2, Bin Wang 1, Mingzhe Song 1, Alicia Hulbert 3, Chen Chen 1, Fenglei Yu 1
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PMID: 32566027 PMCID: PMC7285810 DOI: 10.3892/ol.2020.11592
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Abstract
In the present study, promoter hypermethylation of cysteine dioxygenase type 1 (CDO1) was evaluated in non-small cell lung cancer (NSCLC) tissues to assess the value of CDO1 as a novel biomarker to improve the diagnosis of NSCLC. Tumor tissue samples and corresponding normal lung tissue samples from 42 patients with NSCLC were obtained at the Department of Thoracic Surgery, The Second Xiangya Hospital (Changsha, China). Conventional methylation-specific PCR (cMSP) and methylation-on-beads followed by quantitative methylation-specific PCR (MOB-qMSP) were used to analyze the tumor and normal lung tissue samples. Using these two methods, promoter DNA hypermethylation of the CDO1 gene was detected in 59.4 and 71.0% of tumor tissues of patients with NSCLC and in 9.4 and 0% of normal lung tissue, respectively. Compared with the rate of methylation in the well-differentiated NSCLC tissues (15.4 and 55.6%, respectively), the rate of CDO1 gene promoter methylation was higher in the poorly differentiated tissues (89.5 and 92.3%, respectively). Overall, it was demonstrated that the MOB-qMSP method had a higher positive detection rate for CDO1 hypermethylation compared with the cMSP method. In conclusion, CDO1 gene promoter hypermethylation was more frequently observed in NSCLC tissues compared with in normal lung tissues, and a high methylation frequency of the CDO1 gene in biopsy specimens of NSCLC was associated with the degree of differentiation.

Keywords: cysteine dioxygenase type 1; diagnosis; methylation; methylation-specific PCR; non-small cell lung cancer.

Copyright © 2020, Spandidos Publications.

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Oncol Lett
. 2020 Jul;20(1):962-966. doi: 10.3892/ol.2020.11616. Epub 2020 May 13.
2-Deoxy-D-glucose Enhances the Anti-Cancer Effects of Idarubicin on Idarubicin-Resistant P388 Leukemia Cells
Taisuke Matsuo 1, Yumiko Konya 1, Eri Hirayama 1, Yasuyuki Sadzuka 1
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PMID: 32566026 PMCID: PMC7285881 DOI: 10.3892/ol.2020.11616
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Abstract
Cancer cells switch from mitochondrial oxidative phosphorylation to glycolysis, even in the presence of normal oxygen concentrations. Inhibition of the glycolytic pathway is therefore a critical strategy in cancer therapy. A non-metabolic glucose analog, 2-deoxy-D-glucose (2-DG), has been the focus of research on glycolytic inhibitors for use in cancer treatment. The current study examined the anti-cancer effects of 2-DG on idarubicin (IDA)-resistant P388 (P388/IDA) leukemia cells. P388/IDA cells were established following continuous exposure of IDA to P388 cells. Characterization of P388/IDA cells revealed increased lactate production and glucose consumption compared with P388 parent cells. The results of a cell viability assay determined that 2-DG induces higher toxicity in P388/IDA cells compared with P388 cells. Although 2-DG also exhibits endoplasmic reticulum (ER) stress-inducing activity, the cytotoxic effect of the ER stress inducer, tunicamycin, on P388/IDA cells was lower than that of P388 cells. A combination of 2-DG and IDA enhanced P388/IDA cell death compared with each agent alone. The results indicated that P388 cells activated glycolysis after acquiring IDA resistance and therefore, inhibition of the glycolytic pathway via 2-DG might be a useful strategy for cancer therapy against IDA- resistant leukemia cells.

Keywords: 2-deoxy-D-glucose; apoptosis; glycolysis; leukemia.

Copyright © 2020, Spandidos Publications.

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5
Oncol Lett
. 2020 Jul;20(1):955-961. doi: 10.3892/ol.2020.11625. Epub 2020 May 14.
Promoter Methylation of Tumor Suppressor Genes Induced by Human Papillomavirus in Cervical Cancer
Pattamawadee Yanatatsaneejit 1 2, Kanwalat Chalertpet 3, Juthamard Sukbhattee 1, Irin Nuchcharoen 1, Piyathida Phumcharoen 1, Apiwat Mutirangura 2
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PMID: 32566025 PMCID: PMC7285811 DOI: 10.3892/ol.2020.11625
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Abstract
Cervical cancer is the most fourth common cancer in women worldwide. The E6 and E7 high-risk human papillomavirus (HPV) types are the main cause of this cancer. Several studies have revealed that promoter methylation of tumor suppressor genes is induced by HPV E7. Recently, it was found that HPV16-E7 and the DNA methyltransferase 1 complex could bind at the cyclin A1 (CCNA1) promoter, resulting in CCNA1 promoter methylation. Therefore, there is a need to study other tumor suppressor genes for which HPV may induce promoter methylation. The present study investigated whether HPV induced cell adhesion molecule 1 (CADM1) and death associated protein kinase 1 (DAPK1) promoter methylation. C33a (no HPV infection) and SiHa (HPV 16 infection) cell lines were used for methylation status and expression observation. It was found that CADM1 and DAPK1 promoter methylation, no expression of CADM1 and decreased expression of DAPK1, was presented in SiHa cells. While no promoter methylation of these two genes was observed in C33a cells, with positive expression of the genes. It was subsequently investigated whether E6 and/or E7 could induce promoter methylation and decrease the expression of these two genes. Methylation-specific primer PCR and quantitative PCR were performed to elucidate the promoter methylation status and expression of CADM1 and DAPK1 in C33a cells transfected with HPV16 E6-PCDNA3 or HPV16 E7-PCDNA3.1 myc-his, compared to empty vector-transfected cells. The results showed that HPV E7 could induce CADM1 promoter methylation and decrease the gene expression in HPV E7 transfected C33a cells, while HPV E6 could induce DAPK1 promoter methylation and decrease its expression in C33a cells transfected with HPV E6. Finally, the mechanism by which HPV E7 induced CADM1 promoter methylation was observed by performing chromatin immunoprecipitation; the data showed that E7 induced CADM1 methylation by the same mechanism as that for CCNA1, by binding at the CADM1 promoter, resulting in the subsequent reduction of its expression in cervical cancer.

Keywords: cell adhesion molecule 1; cervical cancer; death associated protein kinase 1; human papillomavirus E6; human papillomavirus E7; promoter methylation.

Copyright © 2020, Spandidos Publications.

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Oncol Lett
. 2020 Jul;20(1):947-954. doi: 10.3892/ol.2020.11602. Epub 2020 May 13.
Abnormal Polarization of Macrophage-Like Cells in the Peripheral Blood of Patients With Glioma
Yawei Guo 1, Wenming Hong 1 2, Pengying Zhang 1, Dafei Han 1, Yilong Fang 1, Jiajie Tu 1, Wei Wei 1
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PMID: 32566024 PMCID: PMC7285800 DOI: 10.3892/ol.2020.11602
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Abstract
Glioma is a type of malignant tumor arising from glial cells of the brain or the spine. Circulation-derived macrophage infiltration is a characteristic of the glioma microenvironment. The polarization status of circulation-derived macrophages in patients with glioma remains unclear. Therefore, the present study aimed to evaluate the polarization status of circulation-derived macrophages in patients with glioma. A total of 40 patients with glioma and 38 healthy volunteers were recruited. The polarization status of macrophage-like cells in the peripheral blood of patients with glioma was evaluated. In addition, the associations between the polarization status of macrophage-like cells and glioma stage or the expression levels of the glioma tumor marker chitinase-3-like protein 1 (also termed YKL-40) were evaluated. The number of macrophage-like cells (CD115+CD1c-CD2-CD15-CD19-CD14+CD16+CD11b+) was higher in the peripheral blood of patients with glioma compared with that of healthy volunteers. There were fewer M1 macrophage-like cells, and more M2 macrophage-like cells were induced in the peripheral blood of patients with glioma compared with healthy controls. Specifically, the number of M2a/M2b macrophage-like cells increased, whereas that of M2c macrophage-like cells decreased in the peripheral blood of patients with glioma compared with healthy controls. The polarization status of macrophage-like cells in patients with glioma was not significantly associated with glioma stage or with the glioma marker YKL-40. Overall, the results of the present study revealed that the polarization status of macrophage-like cells in the peripheral blood of patients with glioma was abnormal, offering potential novel diagnostic and therapeutic targets, such as different macrophage subsets, for glioma.

Keywords: YKL-40; glioma; macrophage; polarization.

Copyright © 2020, Spandidos Publications.

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Oncol Lett
. 2020 Jul;20(1):939-946. doi: 10.3892/ol.2020.11603. Epub 2020 May 13.
Identification and Validation of Seven Prognostic Long Non-Coding RNAs in Oral Squamous Cell Carcinoma
Tingting Miao 1, Qingzong Si 1, Yuan Wei 1, Ruihong Fan 1, Junjie Wang 1, Xiaoli An 1
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PMID: 32566023 PMCID: PMC7285779 DOI: 10.3892/ol.2020.11603
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Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common malignancies worldwide, due to poor diagnosis and treatment. There is increasing evidence that demonstrates the involvement of long non-coding RNAs (lncRNAs) in carcinogenesis and cancer progression. Therefore, the aim of the present study was to explore potential lncRNA-associated features of patients with OSCC as a valuable and independent prognostic biomarker. A total of 268 lncRNA expression profiles and clinical patient information on OSCC were downloaded from The Cancer Genome Atlas database. The clinical information was exploited for prescreening, using Cox regression analysis, and differentially expressed lncRNAs (DElncRNAs) were identified using edgeR software. Using the 'caret' package, the datasets were categorized into test datasets and training datasets, respectively. Through bioinformatics, seven prognostic DElncRNAs were selected. Using the regression coefficients, a risk score based on the seven-DElncRNA signature was developed to assess the prognostic function of key DElncRNAs. According to the median risk score, patients were classified into high-risk and low-risk groups in the training and test datasets. Additionally, receiver operating characteristic (ROC) curve analysis was conducted to evaluate the sensitivity and specificity of the prognostic DElncRNAs, and the optimal cut-off point was obtained from ROC analysis. Based on the optimal cut-off point, the patients were also categorized into high-risk and low-risk groups. Notably, the optimal cut-off point was more sensitive than the median risk score, particularly in the test dataset. The Kaplan-Meier survival and log rank test analysis results indicated that the P-value, based on the optimal cut-off, was less than the median risk cut-off. Additionally, stratified analysis results revealed that the seven-DElncRNAs signature was also independent of OSCC age. Furthermore, the findings of the present study suggested that the seven-DElncRNA signature can be used as a potential prognostic indicator and may have important clinical significance in OSCC.

Keywords: long non-coding RNAs; optimal cutoff; oral squamous cell carcinoma; prognostic biomarkers; robust likelihood-based survival analysis.

Copyright © 2020, Spandidos Publications.

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Oncol Lett
. 2020 Jul;20(1):931-938. doi: 10.3892/ol.2020.11629. Epub 2020 May 14.
Comparison of Risk of Ovarian Malignancy Algorithm and Cancer Antigen 125 to Discriminate Between Benign Ovarian Tumor and Early-Stage Ovarian Cancer According to Imaging Tumor Subtypes
Young-Jae Lee 1, Yong-Man Kim 1, Ji-Sik Kang 1, So-Hyun Nam 1, Dae-Yeon Kim 1, Young-Tak Kim 1
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PMID: 32566022 PMCID: PMC7285867 DOI: 10.3892/ol.2020.11629
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Abstract
The present study aimed to compare the accuracy of the Risk of Ovarian Malignancy Algorithm (ROMA) and cancer antigen (CA)125 to discriminate between benign ovarian tumors and early-stage ovarian cancer according to imaging tumor subtypes associated with post-operative histopathological findings. A total of 1,207 patients who were assessed using the ROMA test due to suspected early-stage ovarian cancer and underwent surgery at Asan Medical Center (Seoul, Korea) between September 2014 and March 2018 were identified. A total of 981 patients who met the inclusion criteria were included in the retrospective analysis. Among the 981 subjects, 816 had benign tumors, 90 had malignant tumors and 75 had borderline tumors. Of the patients diagnosed with ovarian cancer or borderline tumor, 47.3% were judged as high-risk by the ROMA test and 58.2% had CA125 levels of >35 U/ml. The specificity and accuracy of ROMA were higher compared with those of CA125 in pre-menopausal females. However, the superiority of the ROMA test in the identification of malignant ovarian tumors compared with CA125 was only observed in patients with endometriotic-type tumors but not in any of the other tumor subtypes. In the endometriotic type of ovarian tumor, the superiority of the ROMA test compared to CA125 was confirmed in triage of ovarian tumor. However, the sensitivity and specificity of ROMA and CA125 were similar for the other tumor types. Therefore, future development of better tumor-specific biomarkers for triage of ovarian tumor is required.

Keywords: biomarkers; cancer antigen 125; diagnostic techniques; epididymis; ovarian cancer.

Copyright © 2020, Spandidos Publications.

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Oncol Lett
. 2020 Jul;20(1):921-930. doi: 10.3892/ol.2020.11628. Epub 2020 May 14.
Comparison of Long-Term Treatment Outcomes of T2N0M0 Laryngeal Squamous Cell Carcinoma Using Different Treatment Methods
Eun Kyung Jung 1, Seong-Min Jin 1, Jae-Gu Kim 1, Jae-Uk Jung 2, Dong Hoon Lee 1, Joon Kyoo Lee 1, Sang Chul Lim 1, Woong-Ki Chung 2, Hee Kyung Kim 3, Jun-Eul Hwang 3, Hyun-Jeong Shim 3, Woo-Kyun Bae 3, Sang-Hee Cho 3, Ik-Joo Chung 3, Tae Mi Yoon 1
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PMID: 32566021 PMCID: PMC7285832 DOI: 10.3892/ol.2020.11628
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Abstract
Early [stage I and II (T2N0M0)] laryngeal cancer types are currently recommended to be treated with a single modality, consisting of definitive radiation therapy or larynx-preserving surgery. Although the treatment outcomes of stage I are good, the frequency of successful outcomes decreases with T2N0M0. Therefore, the present study investigated the treatment outcomes of different treatment methods in T2N0M0 laryngeal cancer. In total, 83 patients with previously untreated T2N0M0 laryngeal squamous cell carcinoma were enrolled. Patients were grouped by treatment method: Radiation therapy (RT; 27 patients); chemoradiotherapy (CRT; 46 patients) with cisplatin base; and surgery-based therapy (SBT; ten patients). The recurrence rates of the RT, CRT and SBT groups were 44.4, 19.6 and 50%, respectively. Moreover, the local control rates of the RT, CRT and SBT groups were 55.6, 87.0 and 80%, respectively. The CRT group had a significantly lower recurrence rate and higher local control rate compared with the RT group (P<0.05). In the survival analysis, overall and disease-specific survival rate did not differ significantly among the treatment groups. However, 3- and 5-year disease-free survival rates (DFS) of the RT group were both 55%, those of the SBT group were both 50% and those of the CRT group were both 80%. Furthermore, the DFS was significantly higher in CRT group compared with the other groups (P=0.02). Using multivariate analysis with Cox regression, it was found that the treatment method was the most important factor for DFS and had a significant impact in the CRT group. In addition, in patients with glottic cancer with anterior commissure and subglottic invasion, the CRT group had significantly improved DFS compared with the RT group, whereas there was no significant difference between the two groups in patients without subglottic invasion. According to National Cancer Institution Common Toxicity Criteria (version 5.0), more patients had toxicity in the CRT group compared with the RT group. However, in the RT and CRT groups, no patients demonstrated mortality due to toxicity, and treatment-related toxicities were manageable. Collectively, although definitive conclusions could not be established, due to the limitations of this retrospective study, the results suggest that CRT had a positive impact on the local control and DFS rates with manageable toxicity in patients with T2N0M0 laryngeal cancer.

Keywords: chemoradiotherapy; disease-free survival; laryngeal neoplasms; radiotherapy; survival rate.

Copyright © 2020, Spandidos Publications.

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10
Oncol Lett
. 2020 Jul;20(1):914-920. doi: 10.3892/ol.2020.11598. Epub 2020 May 8.
Effects of miR-135a-5p and miR-141 on Proliferation, Invasion and Apoptosis of Colorectal Cancer SW620 Cells
Jian Wang 1, Jing Yang 1, Heng Zhang 1, Yusheng Liao 1, Dan Xu 1, Songlin Ma 1
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PMID: 32566020 PMCID: PMC7286134 DOI: 10.3892/ol.2020.11598
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Abstract
Effects of miR-135a-5p and miR-141 on the biological function of colorectal cancer SW620 cells were investigated. Fifty-four specimens of cancer tissues and 54 specimens of corresponding adjacent tissues in colon cancer patients who were treated in The Central Hospital of Wuhan from March 2014 to March 2015 were collected. RT-PCR was used to detect the expression levels of miR-135a-5p and miR-141 in cancer tissues and adjacent tissues. The miR-135a-5p inhibitor and miR-141 mimic carriers were established. The cell proliferation was detected by CCK8, the invasion ability of cells in vitro was evaluated by Transwell chamber, and cell apoptosis of each group was detected by flow cytometry. The results of RT-qPCR showed that expression levels of miR-135a-5p in colorectal cancer tissues were significantly higher than those in adjacent tissues, the expression levels of miR-141 in colorectal cancer tissues were significantly lower than those in adjacent tissues, and the difference was statistically significant (P<0.001). The cell survival rates of the miR-135a-5p inhibitor group and the miR-141 mimic group were significantly lower than those of the NC group and the blank group 48 and 72 h after transfection (P<0.001). The number of invasive cells in the miR-135a-5p inhibitor group and the miR-141 mimic group was significantly lower than that in the blank group and the NC group (P<0.001). Apoptosis rate was significantly higher than that of the NC group and the blank group (P<0.001). In conclusion, low expression levels of miR-135a-5p and miR-141 in colorectal adenomas suggested that miR-135a-5p and miR-141 could act as tumor suppressors in the development of colorectal adenomas; miR-135a-5p and miR-141 inhibited the proliferation and invasion of colon cancer SW620 cells and promoted apoptosis of colon cancer cells.

Keywords: SW620 cell; apoptosis; colon cancer; invasion; miR-135a-5p; miR-141; proliferation.

Copyright: © Wang et al.

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11
Oncol Lett
. 2020 Jul;20(1):907-913. doi: 10.3892/ol.2020.11620. Epub 2020 May 14.
Expression of lncRNA-HOTAIR in the Serum of Patients With Lymph Node Metastasis of Papillary Thyroid Carcinoma and Its Impact
Lan Wu 1, Yanqing Shi 1, Baoguo Liu 2, Mengting Zhao 1
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PMID: 32566019 PMCID: PMC7285833 DOI: 10.3892/ol.2020.11620
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Abstract
The present study aimed to investigate the expression of long non-coding HOX transcript antisense RNA (lncRNA-HOTAIR) in the serum of patients with lymph node metastasis of papillary thyroid carcinoma (PTC) and the underlying mechanism. A total of 89 patients with PTC at Beijing Geriatric Hospital were recruited in this study. Based on the results of color Doppler ultrasound examination, the patients were evaluated for cervical lymph node metastases, and were thereby divided into a metastasis-negative group and a metastasis-positive group. Quantitative fluorescent PCR was used to assess the expression of HOTAIR in serum samples. The PTC cell line TPC-1 was randomly divided into a control and siRNA group. The control group was transfected with a nonsense sequence, while the siRNA group was transfected with si-HOTAIR. After transfection, cell proliferation was evaluated using the MTT assay, and cell migration and invasion were assessed using the cell scratch assay and Transwell assay. Expression levels of vimentin, E-cadherin and proteins associated with the Wnt/β-catenin signaling pathway were assessed using western blot analysis. Based on the results of the ultrasound examination, 53 patients were allocated to the metastasis-negative group, and 36 to the metastasis-positive group. The expression level of lncRNA-HOTAIR was higher in the metastasis-positive group than that in the metastasis-negative group (P<0.05). Compared with the control group, cell proliferation was reduced while cell migration rate and the number of migrating cells were increased in the siRNA group. Compared with the control group, the expression levels of WIF1 and E-cadherin were significantly increased, while the levels of β-catenin and vimentin were significantly decreased. In conclusion, lncRNA-HOTAIR is overexpressed in the serum of patients with lymph node metastasis of PTC. In vitro experiments showed that HOTAIR promoted the proliferation and metastasis of PTC cells by regulating epithelial-mesenchymal transition (EMT) mediated by the Wnt/catenin pathway. Thus, lncRNA-HOTAIR is proposed as a molecular target for the treatment of lymph node metastasis of PTC.

Keywords: HOTAIR; lncRNA; lymph node metastasis; papillary thyroid carcinoma; ultrasound.

Copyright: © Wu et al.

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12
Oncol Lett
. 2020 Jul;20(1):902-906. doi: 10.3892/ol.2020.11632. Epub 2020 May 18.
Effect of Erlotinib Combined With Cisplatin on IL-6 and IL-12 in Mice With Lewis Lung Cancer
Xu Zhang 1, Jinliang Chen 2, Hongsong Jin 3, Wei Zhao 4, Zhibo Chang 5, Huijing Wu 6
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PMID: 32566018 PMCID: PMC7285801 DOI: 10.3892/ol.2020.11632
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Abstract
Effect of erlotinib combined with cisplatin on tumor growth, interleukin-6 (IL-6) and interleukin-12 (IL-12) in mice with Lewis lung cancer (LLC) was investigated. Forty-four pure inbred SPF C57BL/6J mice were modeled for LLC and randomized into groups A, B, C and D (n=11 each group). Mice in group A were given normal saline, group B was given erlotinib, group C was given cisplatin injection and group D erlotinib combined with cisplatin. Tumor growth of the mice was observed and the tumor mass was measured. Serum IL-6 and IL-12 levels were measured by enzyme-linked immunosorbent assay (ELISA) 40 days later. At different time-points after medication, tumor volume in group D was significantly lower than that in groups A, B and C (P<0.05), and that in groups B and C was significantly lower than that in group A (P<0.05), whereas there was no significant difference between groups B and C (P>0.05). Tumor mass in groups B, C and D was significantly lower than that in group A (P<0.05), and that in group D was significantly lower than that in groups B and C (P<0.05), whereas there was no significant difference between groups B and C (P>0.05). Compared with groups B and C, mice in group D had significantly lower IL-6 level (P<0.05), but significantly higher IL-12 level (P<0.05). There was no significant difference in IL-6 and IL-12 levels between groups B and C (P>0.05). In conclusion, erlotinib combined with cisplatin can inhibit the tumor growth of mice with LLC, and inhibition of IL-6 level and upregulation of IL-12 level may be one of its therapeutic mechanisms.

Keywords: IL-12; IL-6; cisplatin; erlotinib; lung cancer.

Copyright: © Zhang et al.

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13
Oncol Lett
. 2020 Jul;20(1):893-901. doi: 10.3892/ol.2020.11635. Epub 2020 May 18.
Long Non-Coding RNA SNHG7 Inhibits NLRP3-dependent Pyroptosis by Targeting the miR-34a/SIRT1 Axis in Liver Cancer
Zhaohong Chen 1, Miao He 1, Junhua Chen 1, Chao Li 1, Qianshi Zhang 1
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PMID: 32566017 PMCID: PMC7285900 DOI: 10.3892/ol.2020.11635
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Abstract
Long non-coding RNA small nucleolar RNA host gene 7 (SNHG7) is involved in a variety of different types of cancer; however, the role of SNHG7 during liver cancer progression is not completely understood. The aim of the present study was to investigate the functional role and regulatory mechanism underlying SNHG7 during liver cancer. A total of 25 paired hepatocellular carcinoma (HCC) tumor tissues and adjacent normal tissues were collected. Reverse transcription-quantitative PCR and western blotting were performed to detect the expression levels of SNHG7, microRNA (miR)-34a, sirtuin 1 (SIRT1) and pyroptosis-related targets. RNA fluorescence in situ hybridization was performed to detect the expression of SNHG7 in HCC tissues. SNHG7 expression was upregulated in HCC tissues and liver cancer cells compared with normal tissues and normal liver cell lines. High expression of SNHG7 inhibited NLR family pyrin domain containing 3 (NLRP3)-dependent pyroptosis in HepG2 and SK-hep-1 cells. Bioinformatics analysis and dual-luciferase reporter assays were performed to investigate the interactions between miR-34a and SNHG7 or SIRT1. SNHG7 served as a competing endogenous RNA of miR-34a, and SIRT1 was identified as a direct target of miR-34a. Cell pyroptosis was evaluated by TUNEL and lactate dehydrogenase release assays. SNHG7 knockdown reduced SIRT1 expression, but increased the expression levels of NLRP3, caspase-1 and interleukin-1β, leading to pyroptosis. SNHG7 knockdown-induced effects were enhanced by miR-34a upregulation. In summary, the present study indicated that the SNHG7/miR-34a/SIRT1 axis contributed to NLRP3-dependent pyroptosis during liver cancer.

Keywords: hepatocellular carcinoma; microRNA-34a; pyroptosis; sirtuin 1; small nucleolar RNA host gene 7.

Copyright: © Chen et al.

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14
Oncol Lett
. 2020 Jul;20(1):884-892. doi: 10.3892/ol.2020.11634. Epub 2020 May 18.
Associations Between the Expression of SCCA, MTA1, P16, Ki-67 and the Infection of High-Risk HPV in Cervical Lesions
Cuina Han 1 2, Fangfei Zhao 1, Chongyang Wan 1, Yanfang He 1, Yan Chen 1
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PMID: 32566016 PMCID: PMC7286137 DOI: 10.3892/ol.2020.11634
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Abstract
The application of detection technologies for human papillomavirus (HPV) has increased the resection rate for cervical intraepithelial neoplasia and early cervical cancer types. However, a large number of patients still present with advanced cervical cancer upon diagnosis. Therefore, to find a marker for the early diagnosis of cervical cancer, the present study investigated the expression profiles of squamous cell carcinoma antigen (SCCA), tumor metastasis related factor-1 (MTA1), the multiple tumor suppressor gene P16, and the nucleus-associated antigen Ki-67 in cervical lesions, and evaluated the association between the four proteins and the infection of high-risk (HR)-HPV in cervical lesions. The rate of SCCA expression gradually increased with the progression of cervical lesions, but the increase in SCCA expression levels from low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions was not significant (P=0.197). The positive rate of MTA1 expression gradually increased with the development of cervical lesions, but the increase from chronic cervicitis to LSIL was not significant (P=0.258). The positive rates of P16 and Ki-67 expression exhibited significant increasing trends with the progression of cervical lesions. The expression ratio of SCCA between HR-HPV infection and non-infection groups was not statistically significant (P=0.38), but the expression ratios of MTA1, P16 and Ki-67 between HR-HPV infection and non-infection groups were statistically significant (P<0.05). These results demonstrated that the expression of SCCA, MTA1, P16 and Ki-67 increased gradually with the severity of cervical lesions. In addition, there was a positive association between the expression levels of MTA1, P16 and Ki-67 and the infection of HR-HPV in cervical lesions. Therefore, SCCA, MTA1, P16 and Ki-67 may be used to enhance the diagnostic accuracy for cervical lesions.

Keywords: cervical lesions; high-risk human papillomavirus; metastasis-associated gene 1; squamous cell carcinoma antigen.

Copyright: © Han et al.

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15
Oncol Lett
. 2020 Jul;20(1):877-883. doi: 10.3892/ol.2020.11638. Epub 2020 May 18.
A Novel Antitumor Dithiocarbamate Compound Inhibits the EGFR/AKT Signaling Pathway and Induces Apoptosis in Esophageal Cancer Cells
Yun Yang 1 2, Ziyin Tian 1, Xinghua Zhao 1, Ya Li 3, Shuyan Duan 1
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PMID: 32566015 PMCID: PMC7285826 DOI: 10.3892/ol.2020.11638
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Abstract
Dithiocarbamate has been reported to possess a potent antitumor efficacy against several types of cancer, such as ovarian cancer, breast cancer and hepatocellular carcinoma; however, only a few studies have investigated its inhibitory effect on esophageal cancer. Dipyridylhydrazone dithiocarbamate (DpdtC) is a novel dithiocarbamate derivative that was recently designed, synthesized and evaluated in our previous study. In the present study, the cell growth inhibition and apoptosis induced by DpdtC were measured using the CCK-8 and Annexin V-FITC/propidium iodide staining assays, respectively. Epidermal growth factor receptor (EGFR) signaling pathway and apoptosis related protein levels were examined by western blotting. In vivo effect of DpdtC was evaluated in nude mice bearing KYSE-450 ×enograft tumors. The aims of the present study were to further evaluate the antitumor effects of DpdtC on esophageal cancer cells (KYSE-150 and KYSE-450 cells), and to investigate its potential mechanism of action in vitro and in vivo. It was found that DpdtC significantly inhibited KYSE-150 and KYSE-450 cell proliferation by regulating the EGFR/AKT signaling pathway and inducing apoptosis. In addition, this effect was further identified in vivo; DpdtC inhibited the growth of the KYSE-450 esophageal cancer xenografts by regulating the EGFR/AKT signaling pathway. Furthermore, DpdtC did not affect the body weight in mice. Collectively, the present results suggested that DpdtC may be a promising antitumor drug candidate for the treatment of esophageal cancer.

Keywords: AKT; apoptosis; dithiocarbamate; epidermal growth factor receptor; esophageal cancer.

Copyright: © Yang et al.

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16
Oncol Lett
. 2020 Jul;20(1):868-876. doi: 10.3892/ol.2020.11637. Epub 2020 May 18.
Antitumor Immunity Targeting Fibroblast Activation protein-α in a Mouse Lewis Lung Carcinoma Model
Junping Xie 1, Shiyang Yuan 1, Laishui Peng 1, Huanyu Li 1, Linxia Niu 1, Hui Xu 1, Xiaolin Guo 1, Mei Yang 1, Fengying Duan 1
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PMID: 32566014 PMCID: PMC7285819 DOI: 10.3892/ol.2020.11637
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Abstract
The tumor stromal microenvironment is an integral part of the occurrence and development of tumor. Cancer-associated fibroblasts (CAFs) are a key component of most tumor stromal microenvironments. The present study aimed to investigate the use of CAFs-targeted immunotherapy to fibroblast activation protein-α (FAP-α) expressed in CAFs. Recombinant adenoviral vectors containing the mouse FAP-α cDNA (rAd-FAP-α) were constructed. C57BL/6 mice were immunized with rAd-FAP-α infected dendritic cells (DCs) against FAP-α, which is overexpress in CAFs. The results demonstrated that mice vaccinated with rAd-FAP-α DCs gave rise to potent FAP-α-specific cytotoxic T lymphocytes capable of lysing Lewis lung cancer (LLC) CAFs. Furthermore, mice vaccinated with rAd-FAP-α-transduced DCs induced an effective therapeutic or protective antitumor immunity to LLC in a subcutaneous model, and prolonged overall survival time compared with mice vaccinated with the control recombinant adenovirus-transduced DCs (rAd-c DCs) or DCs alone. The results of the present study suggested that FAP-α, which is preferentially expressed in CAFs, may be considered as a potential target for killing or destroying CAFs within the tumor stromal microenvironment, and may be exploited to develop immunogenic tumor vaccines.

Keywords: Lewis lung cancer; antitumor immunity; cancer-associated fibroblast; dendritic cells; fibroblast activation protein α.

Copyright: © Xie et al.

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17
Oncol Lett
. 2020 Jul;20(1):861-867. doi: 10.3892/ol.2020.11626. Epub 2020 May 14.
Open vs. Laparoscopic Surgery for Locally Advanced Gastric Cancer After Neoadjuvant Therapy: Short-term and Long-Term Survival Outcomes
Nianchang Wang 1, Aiping Zhou 2, Jing Jin 3, Huang Huang 4, Yawei Zhang 4, Yingtai Chen 1, Dongbing Zhao 1
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PMID: 32566013 PMCID: PMC7285756 DOI: 10.3892/ol.2020.11626
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Abstract
The aim of the present study was to compare the short-term and long-term survival outcomes of laparoscopic gastrectomy vs. open gastrectomy in treating locally advanced gastric cancer (LAGC) after neoadjuvant therapy. This study retrospectively reviewed the medical records of 270 patients with LAGC, who underwent laparoscopic (n=49) or conventional open (n=221) surgery following neoadjuvant therapy between January 2007 and December 2016 in China National Cancer Center. Postoperative parameters and survival outcomes including overall survival and disease-free survival were analyzed. Patients who underwent laparoscopic gastrectomy (LP) had significantly shorter postoperative stay and a decreased number of metastatic lymph nodes harvested compared to those who underwent open surgery. The 75% disease-free survival (DFS) time in the laparoscopic surgery group (25.7 months) was higher compared with the open surgery group (15.6 months). However, no significant difference was observed in 5-year overall survival and DFS between the two groups. In conclusion, LG provides non-inferior short- and long-term survival outcomes compared with open surgery, suggesting a laparoscopic approach may be justified for patients with LAGC receiving neoadjuvant therapy. More randomized controlled trials are required to investigate the positive effects of LG for LAGC following neoadjuvant therapy.

Keywords: gastric cancer; laparoscopic surgery; long-term survival outcomes; neoadjuvant therapy; short-term outcomes.

Copyright: © Wang et al.

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18
Oncol Lett
. 2020 Jul;20(1):850-860. doi: 10.3892/ol.2020.11593. Epub 2020 May 7.
ASR488, a Novel Small Molecule, Activates an mRNA Binding Protein, CPEB1, and Inhibits the Growth of Bladder Cancer
Ashish Tyagi 1, Venkatesh Kolluru 1, Balaji Chandrasekaran 1, Uttara Saran 1, Arun K Sharma 2, Murali K Ankem 1, Chendil Damodaran 1
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PMID: 32566012 PMCID: PMC7285857 DOI: 10.3892/ol.2020.11593
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Abstract
Due to a lack of mechanistic insights, muscle-invasive bladder cancer (MIBC) remains incurable and is one of the most lethal types of cancer in the United States. The present study investigated changes in the molecular signatures of MIBC cells (TCCSUP and HT1376) after treatment with a novel small molecule, ASR488, to gain knowledge of the mechanisms that inhibited MIBC cell growth. ASR488 treatment initiated apoptotic signaling in MIBC cells. Pathway enrichment analysis was used to analyze the changes in function of differentially expressed genes. Gene Ontology analysis, as well as Kyoto Encyclopedia of Genes and Genomes analysis, was also performed. These analyses along with reactome pathway enrichment analyses indicated that the genes upregulated in the ASR488-treated cells are involved in focal adhesion, neurotrophin signaling, p53 signaling, endoplasmic reticulum functioning in terms of protein processing, and pathways related to bladder cancer. The genes downregulated in ASR488-treated MIBC cells were mainly involved in DNA replication, mismatch repair, RNA degradation, nucleotide excision repair and TGFβ signaling (P<0.05). Furthermore, reverse transcription-quantitative PCR analysis revealed an increase in transcripts of the most upregulated genes in ASR 488-treated MIBC cells: CPEB1 (36-fold), IL11 (30-fold), SFN (20.12-fold) and CYP4F11 (15.8-fold). In conclusion, the analysis of biological functions of the most differentially expressed genes revealed possible mechanisms that may be associated with the aggressiveness of MIBC.

Keywords: CPEB1; apoptosis; differential gene expression; muscle invasive bladder cancer; small molecules.

Copyright: © Tyagi et al.

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19
Oncol Lett
. 2020 Jul;20(1):841-849. doi: 10.3892/ol.2020.11596. Epub 2020 May 7.
Expression of HIF-1α Is a Predictive Marker of the Efficacy of Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer
Bin Yan 1, Quan-Fu Ma 1, Wen-Fu Tan 1, Hong-Ning Cai 1, Yan-Li Li 1, Zhi-Gang Zhou 1, Xuan Dai 1, Fa-Xia Zhu 1, Yu-Jing Xiong 1, Meng Xu 1, Yu-Lin Guo 1, Han Gao 1, Jun-Bo Hu 2, Xu-Feng Wu 1
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PMID: 32566011 PMCID: PMC7285839 DOI: 10.3892/ol.2020.11596
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Abstract
Platinum-based, arterial infusion chemotherapy as a neoadjuvant chemotherapy (NACT) followed by hysterectomy may be efficient for the treatment of locally advanced cervical cancer and improve prognosis. It is important to predict whether the NACT would be effective before it is launched. Hypoxia inducible factor-1α (HIF-1α) is the master transcriptional regulator of the cellular response to altered oxygen concentration. HIF-1α protein expression is elevated in numerous human malignancies, contributes to poor disease outcome, and has been reported to induce tumorigenesis and chemoresistance. In the present study, patients with International Federation of Gynecology and Obstetrics stage IIB-IIIB cervical cancer (n=59) between 2008 and 2014 were assessed for HIF-1α expression by immunohistochemistry. Tumor samples were obtained by biopsy before any treatment. A double-path chemotherapy regimen, paclitaxel (intravenous) plus cisplatin (intra-arterial injection into the uterine region), was used as NACT. The patients were then separated into two groups according to NACT response: One group comprised patients with NACT, for whom the response to treatment was efficient resulting in complete/partial remission of the tumor (CR + PR group; n=52), the other group contained patients with NACT, for whom the result of the treatment was a stable/progressive disease (SD + PD group; n=7). HIF-1α expression was tested in paraffin-embedded sections using immunohistochemistry. HIF-1α expression was significantly higher in the SD + PD group compared with the CR + PR group (P=0.029). The overall survival time was significantly longer in the CR + PR group compared with the SD + PD group (P<0.001). When the patients were divided into two groups based on HIF-1α expression levels. Low (weighted score ≤4, n=39) and high (weighted score ≥6, n=20) expression level groups; the low HIF-1α expression group was significantly more susceptible to NACT treatment (P=0.025). Cox hazard analysis revealed that a high level of HIF-1α expression and lymph node metastases were significant independent predictors of poor overall survival (P=0.025, HR=6.354; P=0.020, HR=6.909, respectively). These results indicated that the expression of HIF-1α may be able to predict the efficiency of NACT and may be considered an independent prognostic factor for stage IIB-IIIB cervical cancer.

Keywords: cervical cancer; hypoxia-inducible factor-1α; neoadjuvant chemotherapy; predictive marker; prognosis.

Copyright: © Yan et al.

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20
Oncol Lett
. 2020 Jul;20(1):828-840. doi: 10.3892/ol.2020.11597. Epub 2020 May 7.
Downregulation of ST3GAL5 Is Associated With Muscle Invasion, High Grade and a Poor Prognosis in Patients With Bladder Cancer
Song Ouyang 1 2, Ji-Hong Liu 1, Zhao Ni 2, Guo-Fu Ding 2, Qin-Zhang Wang 2
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PMID: 32566010 PMCID: PMC7285741 DOI: 10.3892/ol.2020.11597
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Abstract
In patients with bladder cancer (BC), the association between ST3 β-galactoside α-2,3-sialyltransferase 5 (ST3GAL5) expression and clinical outcomes, particularly regarding muscle-invasive disease, high tumor grade and prognosis, remain unknown. In the present study, the expression of ST3GAL5 and its association with clinical outcomes in patients with BC was analyzed using various public bioinformatics databases. The difference in ST3GAL5 expression between BC and healthy bladder tissues was also evaluated using data from the Oncomine database, The Cancer Genome Atlas and Gene Expression Omnibus database. The differences in ST3GAL5 expression between muscle invasive BC (MIBC) and non-muscle invasive BC (NMIBC), and high- and low-grade BC were also analyzed. Furthermore, genes that were positively co-expressed with ST3GAL5 in patients with BC were identified from the intersection between the Oncomine, Gene Expression Profiling Interactive Analysis 2 and UALCAN databases. Enrichment analysis by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Reactome pathway enrichment analyses and a gene-concept network was performed using R package. Gene set enrichment analysis was also performed to assess the signaling pathways influenced by the high and low expression of ST3GAL5 in BC. The results indicated that ST3GAL5 expression was significantly lower in BC tissues compared with normal bladder tissues (P<0.05). Furthermore, ST3GAL5 expression in MIBC and high-grade BC was significantly lower compared with NMIBC and low-grade BC (P<0.05), respectively. The results from Kaplan-Meier survival analysis result demonstrated that ST3GAL5 downregulation was associated with poor survival in patients with BC (P<0.05). Taken together, these findings suggested that ST3GAL5 may be considered as an anti-oncogene in BC, could represent a potential predictive and prognostic biomarker for BC and may be a molecular target for tumor therapy.

Keywords: ST3 β-galactoside α-2,3-sialyltransferase 5; bladder cancer; high grade; methylation; muscle invasive; prognosis.

Copyright: © Ouyang et al.

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21
Oncol Lett
. 2020 Jul;20(1):817-827. doi: 10.3892/ol.2020.11611. Epub 2020 May 13.
Salvia bowleyana Dunn Root Is a Novel Source of Salvianolic Acid B and Displays Antitumor Effects Against Gastric Cancer Cells
Binghua Chen 1, Chaoqun Huang 1 2, Yuanyan Zhang 1, Xiaoqiong Tang 1, Suhuan Li 1, Qingshui Wang 1, Yao Lin 1
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PMID: 32566009 PMCID: PMC7285817 DOI: 10.3892/ol.2020.11611
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Abstract
Salvianolic acid B (Sal-B) is widely used in China for the treatment of numerous diseases. Currently, Salvia miltiorrhiza Bunge is the main source of this compound, but Salvia bowleyana Dunn, a surrogate of S. miltiorrhiza Bge, may provide a novel source for obtaining more Sal-B. In the present study, a simple method for separation and purification of phenolic compounds from S. bowleyana Dunn roots was employed. Sal-B was subsequently purified and its inhibitory effect on the gastric cancer HGC-27 and AGS cell lines was investigated. Sal-B extracted from S. bowleyana Dunn displayed significant antitumor activity in proliferation and apoptosis assays. Overall, it was found that S. bowleyana Dunn has a higher Sal-B content than S. miltiorrhiza Bge and may be used as a novel source of this potential anti-gastric cancer compound.

Keywords: Salvia bowleyana Dunn; Salvia miltiorrhiza Bunge; gastric cancer; salvianolic acid B.

Copyright: © Chen et al.

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22
Oncol Lett
. 2020 Jul;20(1):810-816. doi: 10.3892/ol.2020.11608. Epub 2020 May 13.
Propofol Induces ROS-mediated Intrinsic Apoptosis and Migration in Triple-Negative Breast Cancer Cells
Hao Wang 1 2, Lidong Zhao 3, Jing Wu 4, Jiang Hong 3, Songpo Wang 1
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PMID: 32566008 PMCID: PMC7285815 DOI: 10.3892/ol.2020.11608
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Abstract
Propofol is widely applied in general anesthesia owing to its short effect and rapid recovery. Apart from its anesthetic advantages, propofol has also been observed to inhibit the growth of several types of cancer cells. Breast cancer is the most diagnosed cancer in females worldwide and triple negative breast cancer (TNBC) constitutes 15-20% of all breast cancer cases. TNBC is characterized by a high recurrence rate, which is associated with its high mortality rate. The present study aimed to evaluate apoptosis in MDA-MB-468 cells treated with propofol. The Cell Counting Kit-8 assay was used to assess proliferation in cells treated with different concentrations of propofol. In addition, Annexin V-FITC was used to detect apoptosis. Furthermore, the generation of reactive oxygen species (ROS) was examined. The relative expression of proteins in the intrinsic apoptosis pathway, such as Bak, Bax, Bcl-2, Cytochrome c, apoptotic peptidase-activating factor 1 (Apaf-1), Caspase 3 and Caspase 9, were calculated relative to GAPDH with western blot analysis. A wound healing assay was performed to examine the effect of propofol on MDA-MB-468 cell migration. The present study revealed that propofol inhibited the proliferation and increased the level of ROS in MDA-MB-468 cells. The expression levels of Cytochrome c, Apaf-1, Bax, Bak and cleaved Caspase 3/9 were upregulated compared with GAPDH. The level of Bcl-2 protein was upregulated by propofol at a concentration of 5 µM and downregulated at concentrations of 10 and 20 µM. In the wound-healing assay, propofol reduced the scratch distance and area. Taken together, the results of the present study suggested that propofol may induce ROS-mediated intrinsic apoptosis and promote migration in TNBC cells.

Keywords: intrinsic apoptosis; migration; propofol; reactive oxygen species; triple negative breast cancer.

Copyright: © Wang et al.

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23
Oncol Lett
. 2020 Jul;20(1):803-809. doi: 10.3892/ol.2020.11594. Epub 2020 May 7.
Clinical Significance of COL1A1 and COL1A2 Expression Levels in Hypopharyngeal Squamous Cell Carcinoma
Peiliang Lin 1 2, Peng Tian 1 2, Jiaqi Pang 1 2, Lan Lai 1 2, Gui He 1 3, Yang Song 1 3, Yiqing Zheng 1 2
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PMID: 32566007 PMCID: PMC7285875 DOI: 10.3892/ol.2020.11594
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Abstract
Alterations in collagen type I α1 (COL1A1) and collagen type I α 2 (COL1A2) expression levels have been reported to predict prognosis in various types of cancer. However, the effect of these biomarkers on hypopharyngeal squamous cell carcinoma (HPSCC) is yet to be fully elucidated. The present study aimed to explore the prognostic significance of COL1A1 and COL1A2 expression levels in HPSCC. The expression levels of COL1A1 and COL1A2 in 67 patients with HPSCC were examined using an immunohistochemical assay in a tissue microarray. The associations between COL1A1/COL1A2 expression levels and patient clinicopathological features were analyzed using ANOVA, Pearson's χ2 or Fisher's exact test. The Cox proportional hazard models and Kaplan-Meier survival analysis with log-rank tests were used to analyze the significance of COL1A1/COL1A2 as prognostic markers for patients with HPSCC. As a result, immunohistochemical staining revealed that COL1A1 was positively expressed in all cases, among which 40.3% were strong positive, while COL1A2 was positively expressed in 76.1% of the HPSCC cases with 6.0% of the samples exhibiting strong staining. Further analysis revealed no significant association between the expression levels of COL1A1/COL1A2 and other clinicopathological features. Cox regression analysis revealed that a high COL1A2 expression level predicted a high locoregional recurrence and a less favorable disease-free survival rate (P=0.042 and 0.020, respectively). Overall, the present study indicated that COL1A2 expression levels may have value as a prognostic indicator in HPSCC.

Keywords: COL1A1; COL1A2; hypopharyngeal squamous cell carcinoma; prognosis; tissue microarray.

Copyright: © Lin et al.

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24
Oncol Lett
. 2020 Jul;20(1):794-802. doi: 10.3892/ol.2020.11589. Epub 2020 May 6.
SATB2 Knockdown Decreases Hypoxia-Induced Autophagy and Stemness in Oral Squamous Cell Carcinoma
Weijie Dong 1 2, Yawen Chen 1 2, Naiying Qian 1 2, Guoqi Sima 1 2, Jianming Zhang 1 2, Zhiqin Guo 1 2, Changlin Wang 3
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PMID: 32566006 PMCID: PMC7285822 DOI: 10.3892/ol.2020.11589
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Abstract
Increasing evidence has suggested that special AT-rich sequence-binding protein 2 (SATB2) may be involved in the progression of numerous types of human cancer; however, the biological function of SATB2 in oral squamous cell carcinoma (OSCC) occurrence and progression remains relatively unknown. The present study aimed to investigate the potential role of SATB2 in the regulation of biological characteristics of OSSC during hypoxia. The expression of SATB2 in SCC9 cells was knocked down using small interfering RNA. Western blotting was used to determine the protein expression levels of SATB2, autophagy-related proteins microtubule-associated protein light chain (LC)3-I/II and Beclin-1, and stemness markers such as Oct-4 (POU class 5 homeobox 1), Sox-2 (SRY-box 2) and Nanog (nanog homeobox). Transmission electron microscopy and monodansylcadaverine staining were used to detect the presence of autophagosomes. Furthermore, the self-renewal capacity of cells was analyzed using colony forming assays; the cell proliferative, migratory and invasive ability were evaluated using CCK-8, wound healing and Transwell assays, respectively; and the cell cycle distribution and rate of apoptosis were detected using flow cytometry. The expression levels of SATB2, autophagy-related proteins and stemness markers were significantly increased in SCC9 cells following hypoxic treatment. Meanwhile, the genetic knockdown of SATB2 inhibited hypoxia-mediated autophagy by decreasing the expression levels of Beclin-1, and preventing the conversion of LC3-I to LC3-II and the accumulation of autophagosomes. The knockdown of SATB2 also inhibited the hypoxia-induced colony-forming ability and the expression of stemness markers. Functionally, it also inhibited the proliferative, migratory and invasive abilities of SCC9 cells, while inducing apoptosis and cell cycle arrest under hypoxia. In conclusion, the present study suggested that SATB2 may function as an oncogene in OSCC cells, and targeting SATB2 may be a potential therapeutic strategy for the treatment of OSCC.

Keywords: SATB2; autophagy; invasion; oral squamous cell carcinoma; stemness.

Copyright: © Dong et al.

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25
Oncol Lett
. 2020 Jul;20(1):785-793. doi: 10.3892/ol.2020.11590. Epub 2020 May 6.
Continuous Progression of Hemorrhage of Sphenoid Ridge Meningioma Causing Cerebral Hernia: A Case Report and Literature Review
Song Han 1, Yakun Yang 1, Zuocheng Yang 1, Ning Liu 1, Xueling Qi 2, Changxiang Yan 1, Chunjiang Yu 1
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PMID: 32566005 PMCID: PMC7285884 DOI: 10.3892/ol.2020.11590
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Abstract
The aim of the present study was to explore the clinical characteristics of repeated hemorrhages of meningioma and analyze the causes of hemorrhage. Meningiomas are mostly benign tumors that rarely manifest hemorrhagic strokes. In the present study, a case of sphenoid ridge meningioma with repeated hemorrhages is reported. Internal hemorrhage was first observed, which, on further aggravation, formed a hematoma in the brain parenchyma and finally led to the development of a hernia. No neurological deficit was present after surgery and rehabilitation. A postoperative pathological examination showed increased levels of Ki-67, abnormal blood vessels in the tumors and the presence of progesterone, which indicate possible causes of the hemorrhage. A review of associated previous studies revealed that hemorrhages originate mainly from inside the meningioma. Two cases of meningiomas with repeated hemorrhages have been reported; one in the foramen magnum region and the other in the pineal gland area. The foramen magnum tumor had an interval of 1.33 months between two hemorrhagic episodes. Collecting relevant data from the latter case was not possible. In the present case report, the interval between two bleeding episodes was 3 days. The literature review also revealed that the average age of onset of meningioma is relatively young at only 28.00±6.24 years. In conclusion, repeated hemorrhages in meningiomas are extremely rare and the causes have not yet been identified. Increased Ki-67 and abnormally proliferating blood vessels may be potential causes of hemorrhage. Early diagnosis and rapid surgical intervention are essential to prevent further episodes of bleeding, which may otherwise have fatal consequences for the patients.

Keywords: hemorrhage; magnetic resonance imaging; meningioma; mortality; pathology.

Copyright: © Han et al.

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26
Oncol Lett
. 2020 Jul;20(1):774-784. doi: 10.3892/ol.2020.11595. Epub 2020 May 7.
Long Non-Coding RNA AC023794.4-201 Exerts a Tumor-Suppressive Function in Laryngeal Squamous Cell Cancer and May Serve as a Potential Prognostic Biomarker
Zhisen Shen 1, Jie Yuan 1 2, Qiaoling Tong 3, Wenjuan Hao 1, Hongxia Deng 1, Qun Li 1, Chongchang Zhou 1, Yan Hu 1 2, Jie Xu 1 2
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PMID: 32566004 PMCID: PMC7286120 DOI: 10.3892/ol.2020.11595
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Abstract
After the expression level of lncRNA AC023794.4-201 was upregulated in 2 laryngeal squamous cell carcinoma (LSCC) cell lines (AMC-HN-8 and TU-212) and LSCC xenografts, the biological function of lncRNA AC023794.4-201 in LSCC was further investigated using in vitro and in vivo experiments, such as cell function experiments and nude mice transplantation. In our previous study, it was demonstrated that the expression level of the long non-coding RNA (lncRNA) AC023794.4-201 were decreased in laryngeal squamous cell carcinoma, particularly in cases of LSCC with lymphatic metastasis. Moreover, low expression levels of AC023794.4-201 were revealed to be an adverse prognostic factor for patients with LSCC. In the present study, lentiviruses were used to overexpress AC023794.4-201 before a series of cell function assays were performed and a xenograft nude mouse model was constructed, in order to further investigate the functions of AC023794.4-201 in LSCC. AC023794.4-201 inhibited the proliferation and the cloning capacity of LSCC cells compared with the negative control group as indicated by real-time cell analysis and the plate colony formation assay. Flow cytometry and transwell migration assays demonstrated that AC023794.4-201 inhibited the migration, induced cell cycle arrest and increased the apoptotic rate of LSCC cells. The results of the in vivo studies demonstrated that AC023794.4-201 significantly inhibited the growth of LSCC xenografts, and promoted apoptosis. In conclusion, the findings of the present study suggested that AC023794.4-201 may exert tumor-suppressive functions in the progression of LSCC and may serve as a potential prognostic biomarker for LSCC.

Keywords: AC023794.4-201; laryngeal squamous cell carcinoma; long non-coding RNA; prognostic biomarker.

Copyright: © Shen et al.

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27
Oncol Lett
. 2020 Jul;20(1):765-773. doi: 10.3892/ol.2020.11581. Epub 2020 Apr 28.
Identification of Predictive Factors in Hepatocellular Carcinoma Outcome: A Longitudinal Study
Huiyuan Tian 1, Shaofeng Cao 2, Mingxing Hu 3, Yuzhu Wang 3, Qiang Fu 3, Yanfeng Pan 4, Tao Qin 3
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PMID: 32566003 PMCID: PMC7285798 DOI: 10.3892/ol.2020.11581
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Abstract
Various surgical methods impact the prognosis of patients with hepatocellular carcinoma (HCC) differently. However, clinical guidelines remain inconsistent and the relative importance of predictors of survival outcomes requires further evaluation. The present study aimed to rank the importance of predictive factors that impact the survival outcomes of patients with HCC and to compare the prognosis associated with different surgical methods based on data obtained from the Surveillance, Epidemiology and End Results database. To achieve these aims, the present study used a random forest (RF) model to detect important predictive factors associated with survival outcomes in patients with HCC. Cox regression analysis was used to compare different surgery methods. The variables included in the Cox regression model were selected based on the Gini index calculated by the RF model. Using the RF model, the present study demonstrated that surgery method, tumor size and age were the first, second and third most important factors associated with HCC prognosis, respectively. Overall, patients who underwent local tumor destruction [(hazard ratio (HR)=0.48; 95% confidence interval (CI), 0.45-0.51; P<0.001)], wedge or segmental resection (HR, 0.31; 95% CI, 0.29-0.33; P<0.001), lobectomy (HR, 0.29, 95% CI, 0.27-0.31; P<0.001) or liver transplantation (HR, 0.16; 95% CI, 0.14-0.17; P<0.001) demonstrated improved overall survival time compared with those treated with surgery, with a gradual decreasing trend observed in HRs. The present study demonstrated that the surgical method used is the most important predictor of the survival outcomes of patients with HCC. Liver transplantation resulted in the best prognosis for patients with HCC, except for those with undifferentiated tumors or distant metastasis.

Keywords: carcinoma; data mining; hepatocellular; survival analysis.

Copyright: © Tian et al.

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28
Oncol Lett
. 2020 Jul;20(1):758-764. doi: 10.3892/ol.2020.11579. Epub 2020 Apr 28.
MiR-181a Functions as an Oncogene by Regulating CCND1 in Multiple Myeloma
Xiao Yan 1, Minjie Gao 1, Ping Zhang 1, Guifang Ouyang 1, Qitian Mu 2, Kaihong Xu 1
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PMID: 32566002 PMCID: PMC7286114 DOI: 10.3892/ol.2020.11579
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Abstract
MicroRNA-181a (miR-181a) has been demonstrated to be upregulated in patients with multiple myeloma (MM). In several studies, miR-181a has been demonstrated to be significantly overexpressed in MM; however, its potential role in development and progression of MM remains unknown. In the present study, the functions of miR-181a and the potential underlying molecular mechanisms in the pathogenesis of MM were examined. Increased expression of miR-181a was observed in bone marrow samples from patients with MM and the MM RPMI8226 cell line. The role of miR-181a was examined and it was demonstrated that it participated in the proliferation and migration processes of the MM cell line. Furthermore, it was demonstrated that the downregulation of miR-181a inhibited the expression of CCND1, a cell cycle regulatory gene, and caused cell cycle arrest in MM cells. The results of the present study suggested that miR-181a functions as an onco-miRNA in MM, which serves regulatory roles by upregulating expression of CCND1 and may therefore serve as a potential target in patients with MM.

Keywords: cyclin D1; microRNA-181a; multiple myeloma.

Copyright: © Yan et al.

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29
Oncol Lett
. 2020 Jul;20(1):751-757. doi: 10.3892/ol.2020.11610. Epub 2020 May 13.
miR-203 Affects Esophageal Cancer Cell Proliferation, Apoptosis and Invasion by Targeting MAP3K1
Mingzhu Zong 1, Wanting Feng 1, Li Wan 1, Xiaojuan Yu 1, Weiyong Yu 1
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PMID: 32566001 PMCID: PMC7285942 DOI: 10.3892/ol.2020.11610
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Abstract
miR-203 has been indicated to be a tumor suppressor in esophageal cancer, however, the underlying molecular mechanisms by which it functions are not fully understood. The present study aimed to investigate the molecular mechanisms underlying the regulatory activities of microRNA (miR)-203 in esophageal cancer. The miR-203 mimic/inhibitor, Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) overexpression plasmid and MAP3K1 small interfering (si)RNA were transfected into TE-1 cells. miR-203 and MAP3K1 mRNA expression were detected via reverse transcription-quantitative PCR analysis, while MAP3K1 protein expression was detected via western blot analysis. Dual-luciferase reporter assay was used to determine whether MAP3K1 was a direct target of miR-203. Cell proliferation and invasion abilities were assessed via MTT and Matrigel assays, respectively. Cell apoptosis was analyzed via flow cytometry, Caspase 8/3 Assay kits and western blot analysis. The results demonstrated that MAP3K1 was a direct target of miR-203. Overexpression of MAP3K1 reversed the suppressed cell proliferation and invasion abilities induced by miR-203 mimic, as well as the inhibitory effect of miR-203 mimic on cell apoptosis. Furthermore, MAP3K1 siRNA weakened the effect of miR-203 inhibitor on cell proliferation, apoptosis and invasion.

Keywords: MAP3K1; esophageal cancer; microRNA-203.

Copyright: © Zong et al.

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30
Oncol Lett
. 2020 Jul;20(1):742-750. doi: 10.3892/ol.2020.11633. Epub 2020 May 18.
Clinical Significance and Diagnostic Value of Serum NSE, CEA, CA19-9, CA125 and CA242 Levels in Colorectal Cancer
Hai Luo 1, Kexin Shen 1, Bo Li 1, Ruiqi Li 1, Zeming Wang 1, Zhongshi Xie 1
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PMID: 32566000 PMCID: PMC7286116 DOI: 10.3892/ol.2020.11633
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Abstract
The present study investigated the value of combinations of five specific tumor biomarkers for the diagnosis of colorectal cancer (CRC): Neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cancer antigen (CA)19-9, CA125 and CA242. Associations between these markers and clinicopathological characteristics (including the Tumor-Node-Metastasis stage) were also assessed. Serum levels of the 5 markers were compared between 358 patients with CRC and 298 healthy individuals (CRC and control group, respectively). The NSE concentration of the CRC group was significantly higher compared with the control. Furthermore, patients at clinical stage III+IV exhibited significantly higher NSE levels compared with those at stage I+II. The serum NSE level of N+ patients was significantly higher compared with the N- group, and the NSE level of M1 patients was significantly compared with the M0 group. NSE level was also significantly associated with tumor stage, lymph node metastasis, distant metastasis and hematochezia. The area under the receiver operating characteristic curve (AUC) for NSE in CRC was 0.766, which was significantly higher than that of the other four markers, which ranged from 0.560-0.682. The AUC of NSE, CEA, CA19-9, CA125, CA242 combined was significantly higher compared with any of the markers individually (range, 0.796-0.858). Therefore, serum NSE may be a good clinical tool for the auxiliary diagnosis of colorectal cancer. Besides, the combination of NSE, CEA, CA19-9, CA125 and CA242 was significantly more sensitive compared with NSE alone. Thus, the combined detection of the 5 tumor markers may be more useful for the diagnosis of CRC.

Keywords: colorectal cancer; diagnosis; neuron-specific enolase; prognosis; tumor markers.

Copyright: © Luo et al.

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31
Oncol Lett
. 2020 Jul;20(1):733-741. doi: 10.3892/ol.2020.11624. Epub 2020 May 14.
MicroRNA-32 Promotes Ovarian Cancer Cell Proliferation and Motility by Targeting SMG1
Saitian Zeng 1 2, Shikai Liu 2, Jing Feng 2, Jiefan Gao 2, Fengxia Xue 1
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PMID: 32565999 PMCID: PMC7285996 DOI: 10.3892/ol.2020.11624
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Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy and one of the leading causes of cancer-related deaths among women. Metastasis is the main cause of poor prognosis in OC. MicroRNA (miRNA/miR) has been shown to play an important role in tumorigenesis and metastasis in various cancer types by affecting the expression of its targets. In the present study, the role of miR-32 (miR-32-5p) in OC was explored. Reverse transcription-quantitative PCR results showed that miR-32 expression was significantly upregulated in both OC tissues and cell lines. Inhibition of miR-32 by transfection with miR-32 inhibitor in OC cells markedly suppressed cell proliferation, migration and invasion. In addition, a luciferase assay showed that suppressor of morphogenesis in genitalia 1 (SMG1) is a direct target of miR-32, and interference in SMG1 expression with transfection of SMG1 small hairpin RNA restored miR-32-mediated OC cell proliferation, migration and invasion. Taken together, these results indicate that miR-32 may promote OC cell growth and motility by targeting SMG1. The data of the present study suggest that miR-32 may serve as a potential therapeutic target for OC treatment in the future.

Keywords: microRNA-32; motility; ovarian cancer; proliferation; suppressor of morphogenesis in genitalia 1.

Copyright: © Zeng et al.

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32
Oncol Lett
. 2020 Jul;20(1):724-732. doi: 10.3892/ol.2020.11580. Epub 2020 Apr 28.
Clinical Significance of CD38 and CD101 Expression in PD-1 + CD8 + T Cells in Patients With Epithelial Ovarian Cancer
Jian Zhou 1 2, Wenting Wang 3, Zhiqing Liang 3, Bing Ni 1, Wei He 3, Dan Wang 3
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PMID: 32565998 PMCID: PMC7285834 DOI: 10.3892/ol.2020.11580
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Abstract
Previous studies using mouse liver tumor models have indicated that coexpression of CD38 and CD101 in programmed cell death-1 (PD-1)+CD8+ T cells may reflect fixed dysregulation of CD8+ T cells and thus indicate a poor response to anti-PD-1 immunotherapy. However, whether CD38 and CD101 expression in PD-1+CD8+ T cells can predict the clinical status and efficacy of chemotherapy for various cancer types, including ovarian cancer (OC), remains unclear. In the present study, peripheral blood mononuclear cells (PBMCs) were obtained by Ficoll-Hypaque gradient centrifugation from 96 fresh samples from healthy adult volunteers and patients with epithelial OC, aged 55.21±9.91 years. Additionally, tumor-infiltrating lymphocytes (TILs) were separated using a combination of mechanical, chemical and enzymatic digestion from fresh surgically removed tumor tissues from 15 patients with epithelial OC. The expression of CD38 and CD101 in PD-1+CD8+ T cells or TILs was detected by flow cytometry or immunofluorescence (IF) staining, respectively. The association between the level of CD38/CD101 expression and clinicopathological parameters or postoperative chemotherapy in patients with OC was statistically analyzed. The levels of CD38/CD101-coexpressing PD-1+CD8+ T cells were significantly increased in PBMCs and TILs of patients with OC compared with those of healthy volunteers. The frequency of PD-1+CD38+CD101+CD8+ T cells among the total PD-1+CD8+ T cell subpopulation was negatively associated with clinical stage, lymph node metastasis and postoperative chemotherapy prognosis in patients with OC. Furthermore, IF staining confirmed colocalization of CD38 and CD101 on the majority of TILs in OC tissues. Thus, the present study suggests that coexpression of CD38 and CD101 in peripheral PD-1+CD8+ T cells and TILs may serve as a new indicator for diagnosis and treatment efficacy in patients with epithelial OC.

Keywords: CD101; CD38; diagnosis; ovarian cancer; programmed cell death-1; tumor-infiltrating lymphocytes.

Copyright: © Zhou et al.

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33
Oncol Lett
. 2020 Jul;20(1):715-723. doi: 10.3892/ol.2020.11613. Epub 2020 May 13.
High Levels of Global Genome Methylation in Patients With Retinoblastoma
Hülya Yazici 1 2, Hui-Chen Wu 1, Hulya Tigli 2 3, Elif Z Yilmaz 2 4, Rejin Kebudi 5 6, Regina M Santella 1
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PMID: 32565997 PMCID: PMC7286142 DOI: 10.3892/ol.2020.11613
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Abstract
Retinoblastoma is a tumor of the embryonic neural retina in young children. The DNA methyltransferase 1 (DNMT1) gene has been demonstrated to be transcriptionally activated in cells lacking retinoblastoma 1 (RB1). Thus, there is a direct interaction between DNMT1 and RB1 in vivo. The present study hypothesized that uncontrolled DNMT1, DNMT2 and DNMT3 expression may lead to a high level of global genome methylation causing a second hit or where both alleles are altered, in RB1 and/or inactivation of other genes in retinal cells. To test this, the global genome methylation levels were analyzed in 69 patients with retinoblastoma, as well as 26 healthy siblings and 18 healthy unrelated children as the control groups. Peripheral blood and tumor tissue samples were obtained from 32 patients. The expression levels of DNMT genes were also determined in cell lines. Based on the median levels of global genome methylation in patients, higher genome-wide methylation levels in peripheral blood were associated with a 3.33-fold increased risk for retinoblastoma in patients compared with all healthy controls (95% confidence interval, 0.98-11.35; P<0.0001). The level of global genome methylation and the expression of DNMT genes were increased in the WERI-RB-1 cell line, which has a mutated RB1 gene, compared with a wild-type RB1-expressing cell line. These results supported the hypothesis that epigenetic alterations, as well as mutations in RB1, may be associated with the oncogenesis and inheritance of retinoblastoma. The repression of genes that interact with RB1, such as the DNMT gene family, may be important in patients with retinoblastoma with alterations in RB1, and may serve a role in the treatment and regression of retinoblastoma.

Keywords: DNA methyltransferase genes; gene expression; global genome methylation; retinoblastoma.

Copyright: © Yazici et al.

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34
Oncol Lett
. 2020 Jul;20(1):705-714. doi: 10.3892/ol.2020.11617. Epub 2020 May 13.
Prognostic Significance of High Triglyceride and Apolipoprotein B Levels in Patients With Stage III and High-Risk Stage II Colorectal Cancer Undergoing Curative Surgery
Xiu-Qing Chen 1 2, Pei-Wen Wu 1 2, Dong-Hui Liu 1 2, Sun-Jie Yan 1 2, Xi-Mei Shen 1 2, Li-Yong Yang 1 2
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PMID: 32565996 PMCID: PMC7285852 DOI: 10.3892/ol.2020.11617
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Abstract
Although epidemiologic studies suggest that dyslipidemia increases the risk of colorectal cancer (CRC), the prognostic value of blood lipid and apolipoprotein levels in CRC remains unclear. The aim of the present study was to investigate the impact of blood lipid and apolipoprotein levels on the prognosis of patients with stage III and high-risk stage II CRC undergoing curative surgery. Preoperative levels of total cholesterol, triglycerides (TG), high-density lipoprotein, low-density lipoprotein, very-low-density lipoprotein, apolipoprotein A1 and apolipoprotein B (APO-B) in patients with CRC undergoing surgery were evaluated. The cut-off values of these factors were determined by the maximal x2 method and were used to classify patients into two prognostic groups: Poor and good prognosis groups. The patients prognostic values were assessed using the Kaplan-Meier curve and Cox regression analysis. In addition, the impact of these parameters on the prognosis and their predictive accuracy were evaluated using nomograms and Harrells concordance index, respectively. In total, 246 patients were included in this evaluation. Based on the cut-off points for TG (1.53 mmol/l in men and 1.58 mmol/l in women) and APO-B (0.73 mmol/l in men and women), the present study determined that both TG and APO-B were predictors of disease-free survival (DFS) and overall survival (OS). Multivariate analysis demonstrated that high TG (men, ≥1.53 mmol/l; women, ≥1.58 mmol/l) and high APO-B (≥0.73 mmol/l) levels were significantly associated with decreased DFS and OS. Nomograms that included values for TG and APO-B levels demonstrated higher predictive accuracy compared with that of nomograms without these values. These results indicated that TG and APO-B levels may be good independent prognostic biomarkers after radical CRC surgery. Therefore, adjusting these parameters to moderate levels may be beneficial.

Keywords: apolipoprotein B; colorectal cancer; lipids; survival; triglycerides.

Copyright: © Chen et al.

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35
Oncol Lett
. 2020 Jul;20(1):699-704. doi: 10.3892/ol.2020.11621. Epub 2020 May 14.
Diagnostic Value of NSE Factor Combined With Ultrasound Hemodynamic Indexes in Cervical Lymph Node Metastasis of Lung Cancer
Yansong Li 1, Yong Kuang 2, Yanzhen Jia 2, Shufang Bai 3
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PMID: 32565995 PMCID: PMC7285818 DOI: 10.3892/ol.2020.11621
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Abstract
Value of neuron-specific enolase (NSE) factor combined with ultrasound hemodynamic parameters in the diagnosis of cervical lymph node metastasis of lung cancer was explored. The clinical data of 85 patients with lung cancer, admitted to Qingdao Municipal Hospital (Group) from January 2015 to December 2016, were retrospectively analyzed. According to the results of pathological examination, 47 patients with cervical lymph node metastasis were enrolled in the metastatic group and 38 patients without lymph node metastasis were enrolled in the non-metastatic group. The expression level of NSE in serum and the hemodynamic indicators of blood flow resistance index (RI) and pulsatility index (PI) were compared between the two groups. ROC curve analysis was used to analyze the diagnostic efficacy of NSE, RI, PI, and their combination in lymph node metastasis of lung cancer. The NSE, RI and PI indexes in the metastatic group were significantly higher than those in the non-metastatic group (P<0.05). The sensitivity and specificity of NSE in the diagnosis of cervical lymph node metastasis of lung cancer were 73.68 and 72.34%, respectively; the sensitivity and specificity of RI were 78.95 and 80.85%, respectively; the sensitivity and specificity of PI were 81.58 and 68.09%, respectively. Also, the sensitivity and specificity of NSE combined with RI were 89.47 and 61.70%, respectively, and the diagnostic AUC was 0.881. The sensitivity and specificity of NSE combined with PI were 92.11 and 74.47%, respectively, and the diagnostic AUC was 0.905. NSE, RI, and PI have certain diagnostic value for cervical lymph node metastasis of lung cancer, however, the combined diagnosis is more valuable, and can be used as the auxiliary diagnosis of cervical lymph node metastasis of lung cancer.

Keywords: blood flow pulsation index; blood flow resistance index; lung cancer; lymph node metastasis; neuron-specific enolase.

Copyright: © Li et al.

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36
Oncol Lett
. 2020 Jul;20(1):693-698. doi: 10.3892/ol.2020.11631. Epub 2020 May 15.
Diagnostic Value and Imaging Features of Multi-Detector CT in Lung Adenocarcinoma With Ground Glass Nodule Patients
Jun Lu 1, Haitao Tang 2, Xinguo Yang 1, Lei Liu 1, Minxia Pang 1
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PMID: 32565994 PMCID: PMC7285889 DOI: 10.3892/ol.2020.11631
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Abstract
This study investigated the application value and imaging features of multi-detector CT (MDCT) in the treatment of lung adenocarcinoma with ground glass nodules (GGN). The medical data of 168 patients with pulmonary GGN in Shengli Oilfield Central Hospital from January 2013 to June 2015 were analyzed. Patients with microinvasive adenocarcinoma and invasive adenocarcinoma were included in group A (invasive lung adenocarcinoma, n=98), while patients with atypical adenomatous hyperplasia and adenocarcinoma in situ were included in group B (pre-invasive lung adenocarcinoma, n=70). The imaging features of MDCT were compared. ROC curves of the size of nidus and the size of solid component were drawn for the diagnosis of invasive lung adenocarcinoma. Logistic multivariate regression analysis was used to analyze the risk factors that affected invasive lung adenocarcinoma. There were significant differences in nidus, burr, and lobes of the patients between groups A and B. The size of nidus and the size of solid component of the patients in group A were significantly higher than those of the patients in group B. The AUCs of the size of the nidus and the size of the solid component of the invasive lung adenocarcinoma were 0.891 and 0.902, respectively. The AUC of the combined diagnosis was 0.984. Size of the nidus, size of the solid component, nature of the lesion, burr, and lobes were all risk factors for invasive lung adenocarcinoma. In patients with GGN, size of the nidus and size of the solid component can be used as excellent diagnostic parameters for invasive lung adenocarcinoma, and nidus size (≥9.8 mm), size of the solid component (≥0.9 mm), the mixed GGN nature of the nidus, burr and lobes can distinguish invasive lung adenocarcinoma and pre-invasive lesions.

Keywords: diagnostic value; ground glass nodule; imaging feature; invasive lung adenocarcinoma; multi-detector CT; pre-invasive lung adenocarcinoma.

Copyright: © Lu et al.

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37
Oncol Lett
. 2020 Jul;20(1):685-692. doi: 10.3892/ol.2020.11639. Epub 2020 May 18.
Long Non-Coding RNA NPBWR1-2 Affects the Development of Ovarian Cancer via Multiple microRNAs
Shasha Liu 1, Qiuyue Du 2, Yang Rao 3, Caiyan Liu 3, Pengpeng Qu 4
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PMID: 32565993 PMCID: PMC7285903 DOI: 10.3892/ol.2020.11639
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Abstract
Ovarian cancer has a high incidence rate and mortality in gynaecologic malignancies. Epithelial ovarian cancer (EOC) accounts for >95% of ovarian cancer cases. Most of the patients with EOC are difficult to diagnose in early stage. The aim of the present study was to compare the long non-coding (lnc)RNA expression profiles of five ovarian cancer cell lines (IGROV1, A2780, SKOV3, ES2, and Hey) and an ovarian epithelial cell line (IOSE80) in order to identify differentially expressed lncRNAs and their associated microRNAs (miRNAs). The expression profiles of lncRNAs and mRNAs in these cell lines were determined by microarray gene analysis and reverse transcription-quantitative PCR. lncRNA neuropeptides B and W receptor 1-2 (NPBWR1-2) overexpression was induced in the SKOV3 cell line. Cell viability, proliferation, migration, invasion and apoptosis were evaluated using MTT, colony-formation, Transwell and flow cytometry assays, respectively. The microarray results indicated that several lncRNAs were differentially expressed in the five ovarian cancer cell lines compared with the normal ovarian epithelial cell line. Compared with IOSE80, lncRNA NPBWR1-2 was downregulated by more than two-fold in all five ovarian cancer cell lines. Moreover, NPBWR1-2 overexpression in the SKOV3 cell line decreased cell viability, inhibited proliferation, migration and invasion, and promoted apoptosis compared with the control cells. A total of 20 miRNAs, which are involved in tumorigenesis and development, were predicted to be associated with NPBWR1-2 by bioinformatics analysis. The results of the present study suggest that lncRNA NPBWR1-2 affects the occurrence and development of ovarian cancer via multiple miRNAs, providing a theoretical basis for the development of novel clinical treatments.

Keywords: lncRNA; miRNA; microarray; neuropeptides B and W receptor 1–2; ovarian cancer.

Copyright: © Liu et al.

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38
Oncol Lett
. 2020 Jul;20(1):677-684. doi: 10.3892/ol.2020.11636. Epub 2020 May 18.
Genomic DNA Methylation Profiling Indicates Immune Response Following Thermal Ablation Treatment for HBV-associated Hepatocellular Carcinoma
Yanan Zhao 1 2, Kang Li 1, Jianping Sun 1, Ning He 2, Peng Zhao 2, Chaoran Zang 1 2, Xiaozhen Yang 2, Caixia Hu 2, Jiang Long 2, Honghai Zhang 2, Qi Wang 1 2, Yan Zhao 3, Yonghong Zhang 1 2
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PMID: 32565992 PMCID: PMC7285841 DOI: 10.3892/ol.2020.11636
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Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is the most common type of liver cancer in China. Thermal ablation is one of the main strategies for HCC treatment. However, few studies have investigated the properties of the immune response following thermal ablation thus far. In the present study, five subjects with HBV-associated HCC were recruited from The Beijing Youan Hospital. Peripheral blood mononuclear cells (PBMCs) were collected at three time points: Prior to thermal ablation (PR), 1-3 days post-ablation (P1) and 5-7 days post-ablation (P7). An Illumina 850K methylation microarray was employed to determine the DNA methylation profile of each sample. Data were analyzed using different methylation probes with the Bioconductor package in R. Following annotation of different methylation CG sites (CGs), the associated genes were subjected to an Ingenuity Pathway Analysis. A total of 3,000 significantly different CGs (adjusted P<0.05; |log(fold-change)|>0.5) were identified within the PR, P1 and P7 time points. Of these, 744 (24.8%) sites increased between the PR and P1 time points but gradually decreased at the P7 time point. The remaining 2,256 (75.2%) sites decreased between the PR and P1 time points gradually increased at the P7 time point. Following gene annotation of different CGs on the promoter, signaling pathways analysis demonstrated that 'p70S6K signaling', 'CXCR4 signaling', 'dendritic cell maturation', 'production of nitric oxide and reactive oxygen species in macrophages' pathways were activated at the P7 time point. The present study suggested that PBMC DNA methylation had changed soon after thermal ablation for subjects with HBV-associated HCC, and systemic immune responses were activated, particularly at the P7 time point.

Keywords: DNA methylation; HCC; PBMCs; immune response.

Copyright: © Zhao et al.

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39
Oncol Lett
. 2020 Jul;20(1):667-676. doi: 10.3892/ol.2020.11585. Epub 2020 May 4.
Garcinol Acts as an Antineoplastic Agent in Human Gastric Cancer by Inhibiting the PI3K/AKT Signaling Pathway
Yuanyuan Zheng 1, Chuanyong Guo 2, Xiaoping Zhang 1, Xiaoli Wang 1, A'Huo Ma 1
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PMID: 32565991 PMCID: PMC7285879 DOI: 10.3892/ol.2020.11585
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Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide; however, treatment options other than surgery remain limited. Neoadjuvant chemotherapy has the potential to suppress of gastric tumorigenesis. Garcinol has been reported to exert inhibitory effects on the progression of numerous carcinomas. However, its effects in GC remain unclear. Therefore, the aim of the present study was to investigate the effects of garcinol on the proliferation, invasion and apoptosis of gastric carcinoma cells and then to explore the underlying mechanisms. Garcinol significantly decreased the proliferation and invasion of GC cells and increased apoptosis in a dose-dependent manner. Additionally, the expression of AKTp-Thr308, cyclin D1, Bcl-2, BAX, matrix metalloprotease (MMP-2) and MMP-9 in HGC-27 cells following treatment with garcinol. The results obtained in the present study suggested that garcinol may inhibit gastric tumorigenesis by suppressing the PI3K/AKT signaling pathway.

Keywords: AKT; PI3K; apoptosis; garcinol; gastric cancer; invasion; proliferation.

Copyright: © Zheng et al.

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40
Oncol Lett
. 2020 Jul;20(1):655-666. doi: 10.3892/ol.2020.11606. Epub 2020 May 13.
Histology and Its Prognostic Effect on KRAS-mutated Colorectal Carcinomas in Korea
Hye Seung Lee 1, Dae Yong Hwang 2, Hye Seung Han 3
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PMID: 32565990 PMCID: PMC7285809 DOI: 10.3892/ol.2020.11606
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Abstract
KRAS mutation is frequently identified in advanced colorectal carcinoma (CRC); however, its prognostic significance and the associated histological features have remained to be clarified. In the present study, the precise histological results and prognostic value of KRAS-mutated CRCs were investigated in patients from South Korea. A retrospective review of the results from KRAS mutation testing, as well as evaluation of the histology of 310 cases of CRC at various stages, were performed. Cross-tabulation and survival analysis were performed according to the KRAS status. Patients with KRAS mutation more frequently exhibited serrated and papillary architectures (P=0.009 and P=0.014, respectively). KRAS mutation was an independent unfavorable prognostic factor for overall survival (OS) according to multivariate analysis (P=0.001), whereas no association was observed with disease-free survival (DFS) (P=0.611). Of note, in the subgroup of KRAS-mutated carcinomas, the presence of a solid component on histology was associated with less favorable OS (P=0.032). Furthermore, among the wild type cases, patients with a micropapillary component had a worse OS than those who did not (P=0.018). However, no subgroup or specific histological features were associated with DFS. In summary, KRAS-mutated CRCs had a moderate association with particular histological features, and according to the KRAS mutational status, there was a certain degree of association between histology and prognosis.

Keywords: KRAS; colorectal carcinoma; histology; mutation; prognosis.

Copyright: © Lee et al.

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41
Oncol Lett
. 2020 Jul;20(1):647-654. doi: 10.3892/ol.2020.11630. Epub 2020 May 14.
P2Y 2 R Has a Significant Correlation With Notch-4 in Patients With Breast Cancer
Dong Chul Kim 1, Hana Jin 2, Jong Sil Lee 1, Euna Son 3, Gyeong Won Lee 4, Hye Jung Kim 2
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PMID: 32565989 PMCID: PMC7286009 DOI: 10.3892/ol.2020.11630
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Abstract
Our previous study found that highly metastatic breast cancer cells, such as MDA-MB-231 cells, release higher levels of ATP and exhibit greater P2Y2 receptor (P2Y2R) activity than lowly metastatic breast cancer cells, and that P2Y2R activation mediated by ATP plays a significant role in tumor progression and metastasis. In addition, we reported that radiotherapy-resistant (RT-R) breast cancer cells promote invasion and tumor growth through the activation of P2Y2R by ATP released from RT-R-breast cancer cells than breast cancer cells. Moreover, increased numbers of cancer stem cells (CSCs) were observed among the RT-R-breast cancer cell population. Therefore, in this study, we investigated the expression level of five CSC markers (CD24, CD44, Oct3/4, Notch-4 and ALDH1A1) as well as P2Y2R in the tumor tissues of patients with breast cancer and determined which CSC marker correlates with P2Y2R in breast cancer. According to the immunohistochemical analysis, CD44, Oct3/4 and Notch-4 but not ALDH1A1 were significantly expressed in the tumor tissues (n=180) compared with the normal epithelial tissues (n=20) of patients with breast cancer. It was demonstrated that P2Y2R expression was increased in tumor tissues of patients with breast cancer compared with normal epithelial tissue. Notably, it was identified that P2Y2R expression has a significant correlation with only the CSC marker Notch-4 in patients with breast cancer. The results of this study suggested for the first time to the best of our knowledge that Notch-4 has a notable correlation with P2Y2R, which has important roles in tumor progression and metastasis.

Keywords: CD44; CSC markers; Notch-4; Oct3/4; P2Y2 receptor; breast cancer.

Copyright: © Kim et al.

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42
Oncol Lett
. 2020 Jul;20(1):639-646. doi: 10.3892/ol.2020.11615. Epub 2020 May 13.
PRR11 and SKA2 Promote the Proliferation, Migration and Invasion of Esophageal Carcinoma Cells
Jie Chen 1, Hong-Mei Yang 1, Hui-Chong Zhou 2, Rui-Rui Peng 1, Zhao-Xiao Niu 1, Chun-Yan Kang 1
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PMID: 32565988 PMCID: PMC7285799 DOI: 10.3892/ol.2020.11615
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Abstract
Proline-rich protein 11 (PRR11) together with its upstream adjacent gene, spindle and kinetochore associated 2 (SKA2), represent a classic, head-to-head gene pair. The role of the PRR11 and SKA2 gene pair has been described in various types of cancer, including breast cancer, non-small cell lung cancer, hepatocellular carcinoma and ovarian carcinoma. However, its role in esophageal carcinoma (ESCC) remains unclear. The mRNA expression levels of PRR11 and SKA2 were examined in ESCC surgical specimens. In addition, the role of PRR11 and SKA2 in the proliferation and migratory and invasive capacities of EC9706 and EC109 cell lines was examined. The results from the present study demonstrated that PRR11 and SKA2 expression levels were upregulated in ESCC tissues compared with adjacent normal tissues. Furthermore, PRRl1 and SKA2 knockdown significantly inhibited the proliferation and migratory and invasive capacities of ESCC cells. Conversely, PRRl1 and SKA2 overexpression significantly promoted the proliferation and migratory and invasive capacities of ESCC cell lines via activation of the AKT signaling pathway and certain markers of epithelial-mesenchymal transition, including Snail and N-cadherin. The results from the present study suggested that the PRR11 and SKA2 gene pair may represent a potential target in the diagnosis and treatment of ESCC.

Keywords: PRR11; SKA2; esophageal carcinoma; progression.

Copyright: © Chen et al.

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43
Oncol Lett
. 2020 Jul;20(1):631-638. doi: 10.3892/ol.2020.11640. Epub 2020 May 18.
Downregulation of CLCA4 Expression Is Associated With the Development and Progression of Colorectal Cancer
Lihui Wei 1 2, Wujin Chen 3, Jinyan Zhao 1 2, Yi Fang 1 2, Jiumao Lin 1 2
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PMID: 32565987 PMCID: PMC7285744 DOI: 10.3892/ol.2020.11640
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Abstract
The molecular mechanisms involved in the development and progression of colorectal cancer (CRC) are not completely understood. The present study aimed to identify potential novel genes involved in the development and progression of CRC. Database analysis revealed that the mRNA level of the chloride channel accessory 4 (CLCA4) was frequently lower in primary tumor tissues compared with that in corresponding non-cancerous colon tissues, and was even lower in liver metastases than in primary tumors. Further analyses through The Human Protein Atlas (THPA) website and immunohistochemistry (IHC)-based tissue microarray (TMA) confirmed that CLCA4 mRNA and protein expression were downregulated in CRC tissues. Furthermore, IHC-based TMA analysis revealed a gradual decrease in CLCA4 protein expression among colorectal normal, adenoma and carcinoma tissues. Survival analysis revealed that the decrease in CLCA4 mRNA expression was associated with the overall survival rate of patients with different types of tumor, including CRC, breast cancer, head and neck cancer and stomach cancer. Overall, downregulated CLCA4 expression may influence the development and progression of CRC.

Keywords: CLCA4; colorectal cancer; development; prognosis; survival.

Copyright: © Wei et al.

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44
Oncol Lett
. 2020 Jul;20(1):611-622. doi: 10.3892/ol.2020.11618. Epub 2020 May 13.
Elevated Levels of IL-17A and IL-35 in Plasma and Bronchoalveolar Lavage Fluid Are Associated With Checkpoint Inhibitor Pneumonitis in Patients With Non-Small Cell Lung Cancer
Yi Na Wang 1, Dan Feng Lou 2, Dan Yang Li 3, Wei Jiang 1, Jing Yin Dong 4, Wei Gao 4, Hong Chao Chen 5
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PMID: 32565986 PMCID: PMC7285943 DOI: 10.3892/ol.2020.11618
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Abstract
Advances in the immunology have identified that interleukin (IL)-17 and IL-35 are cytokines with diverse functions, serving important roles in autoimmune diseases and chronic inflammation. Checkpoint inhibitor pneumonitis (CIP) is focal or diffuse lung inflammation induced by immune checkpoint inhibitors and the underlying pathogenesis has not been fully explored. The aim of the present study was to investigate the roles of IL-17A and IL-35, and the correlation between their levels and different T cell subsets in CIP. The levels of IL-17A and IL-35 in peripheral blood and bronchoalveolar lavage fluid (BALF) were measured in patients with non-small cell lung cancer (NSCLC) with CIP, and the corresponding controls. The percentages of helper T lymphocyte (Th)1, Th2 and Th17 cells, and regulatory T cells (Tregs) in the peripheral blood were synchronically detected. Serum levels of IL-17A and IL-35 were significantly increased at the time of CIP diagnosis compared with the baseline, and significantly decreased upon clinical recovery or improvement. IL-17A and IL-35 were also increased in the BALF during the development of CIP compared with the baseline. Serum levels of IL-17A were positively correlated with the percentages of Th1 and Th17 cells as well as the ratio of Th17 to Tregs, but negatively associated with the frequency of Tregs in CIP. Serum levels of IL-35 were positively correlated with the percentages of Th1 and Tregs, and with the ratio of Th1 to Th2 cells in CIP. A higher frequency of Th1 and Th17 cells, as well as higher ratios of Th17 to Tregs and Th1 to Th2 cells were detected upon development of CIP comparing with the baseline. These data suggested that the activation of Th1 and Th17 cells, as well as Treg inhibition contributed to the imbalanced ratios of Th1 to Th2 and Th17 to Tregs, which resulted in increased secretion of IL-17A and IL-35 in the plasma and BALF; this may present a valuable index to monitor the development and severity of CIP in patients with NSCLC receiving immunotherapy.

Keywords: CIP; IL-17; IL-35; NSCLC; immunotherapy.

Copyright: © Wang et al.

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45
Oncol Lett
. 2020 Jul;20(1):601-610. doi: 10.3892/ol.2020.11619. Epub 2020 May 13.
lncRNA KCNQ1OT1 Knockdown Inhibits Colorectal Cancer Cell Proliferation, Migration and Invasiveness via the PI3K/AKT Pathway
Qiaobin Duan 1, Lianxu Cai 2, Kehong Zheng 2, Chunhui Cui 2, Renli Huang 2, Zheng Zheng 2, Lang Xie 2, Cheng Wu 2, Xiang Yu 2, Jinlong Yu 2
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PMID: 32565985 PMCID: PMC7286112 DOI: 10.3892/ol.2020.11619
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Abstract
Colorectal cancer (CRC) is one of the most common primary malignancies worldwide. Numerous studies have demonstrated that long non-coding RNAs (lncRNAs) are considered as crucial regulators of tumor progression. In particular, upregulation of the lncRNA KCNQ1OT1 was reported in various types of malignancy as a promoter of tumor progression. However, the role and underlying mechanism of KCNQ1OT1 in CRC remain unclear. Thus, the present study aimed to investigate the role of KCNQ1OT1 in colorectal cancer through GEPIA, reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses, and cell assays. GEPIA analysis demonstrated that high expression levels of KCNQ1OT1 in CRC tissues predicted a poor prognosis for patients with CRC. KCNQ1OT1 was overexpressed in CRC tissues and cell lines via RT-qPCR analysis. Furthermore, the results from the cell viability assay, colony formation assay, wound healing assay, invasion assay and flow cytometric analysis demonstrated that KCNQ1OT1 knockdown significantly inhibited CRC cell proliferation, migration and invasiveness, and promoted CRC cell apoptosis, leading to cell cycle arrest. Western blot analysis demonstrated that KCNQ1OT1 knockdown inhibited the PI3K/AKT signaling pathway. These results suggest that KCNQ1OT1 may act as an oncogene through the PI3K/AKT signaling pathway in CRC.

Keywords: KCNQ1OT1; PI3K/AKT; colorectal cancer; migration; proliferation.

Copyright: © Duan et al.

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46
Oncol Lett
. 2020 Jul;20(1):589-600. doi: 10.3892/ol.2020.11609. Epub 2020 May 13.
Exosomes Derived From Endoplasmic Reticulum-Stressed Liver Cancer Cells Enhance the Expression of Cytokines in Macrophages via the STAT3 Signaling Pathway
Chengqun He 1 2, Wei Hua 3, Jiatao Liu 1 3, Lulu Fan 1, Hua Wang 1 4, Guoping Sun 1
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PMID: 32565984 PMCID: PMC7285763 DOI: 10.3892/ol.2020.11609
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Abstract
Previous studies have shown that endoplasmic reticulum (ER) stress serves an important role in shaping the immunosuppressive microenvironment by modulating resident immune cells. However, the communication between ER-stressed tumor cells and immune cells is not fully understood. Exosomes have been reported to play a vital role in intercellular communication. Therefore, in order to investigate the role of ER stress-related exosomes in liver cancer cells mediated macrophage function remodeling, immunohistochemical analysis, western-blotting immunofluorescence and cytokine bead array analyses were performed. The results demonstrated that glucose-regulated protein 78 (GRP78) expression was upregulated in human liver cancer tissue. Moreover, 69.09% of GRP78-positive liver cancer tissues possessed macrophages expressing CD68+ (r=0.55; P<0.001). In addition to these CD68+ macrophages, interleukin (IL)-10 and IL-6 expression levels were increased in liver cancer tissues. It was also demonstrated that exosomes released by ER-stressed HepG2 cells significantly enhanced the expression levels of several cytokines, including IL-6, monocyte chemotactic protein-1, IL-10 and tumor necrosis factor-α in macrophages. Furthermore, incubation of cells with ER stress-associated exosomes resulted inactivation of the Janus kinase 2/STAT3 pathway, and inhibition of STAT3 using S3I-201 in RAW264.7 cells significantly reduced cytokine production. Collectively, the present study identified a novel function of ER stress-associated exosomes in mediating macrophage cytokine secretion in the liver cancer microenvironment, and also indicated the potential of treating liver cancer via an ER stress-exosomal-STAT3 pathway.

Keywords: endoplasmic reticulum stress; exosome; inflammation; liver cancer; macrophage.

Copyright: © He et al.

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47
Oncol Lett
. 2020 Jul;20(1):581-588. doi: 10.3892/ol.2020.11622. Epub 2020 May 14.
PSMD9 Expression Correlates With Recurrence After Radiotherapy in Patients With Cervical Cancer
Frank Köster 1, Lisa Sauer 1, Friederike Hoellen 1, Julika Ribbat-Idel 2, Karen Bräutigam 1, Achim Rody 1, Constanze Banz-Jansen 3
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PMID: 32565983 PMCID: PMC7285846 DOI: 10.3892/ol.2020.11622
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In the current retrospective cohort study, the expression of the Proteasome 26S non-ATPase Subunit 9 (PSMD9) was investigated in 102 patients with cervical cancer. The rat homologue of PSMD9, Bridge-1, was identified as a binding protein of the transcription factors PDX-1 and E-12 via its PDZ-domain. The aim of the current study was to evaluate the prognostic or predictive value of PSMD9 expression as a biomarker for patients with cervical cancer. Tissue microarrays were constructed from formalin-fixed paraffin-embedded tissue specimens of cervical cancer and peritumoral stroma after hysterectomy and a Bridge-1 antibody was used to perform immunohistochemistry. The immunoreactions were analyzed using an immunoreactive score, which evaluated the number of positive cells as well as their intensity of PSMD9 expression. A misinterpretation of statistically significant results after multiple testing was controlled by the false discovery rate correction using the algorithm of Benjamini and Hochberg. All tumor tissues and almost all peritumoral stroma tissues expressed PSMD9. The PSMD9 expression in tumor tissues was significantly higher compared with the peritumoral stroma. PSMD9 expression correlated significantly with the expression of the proliferation marker MIB-1. Patients with stronger PSMD9 expression tended to exhibit a higher odds ratio for the recurrence of the disease in all patients (n=102) as well as in the subgroup of 47 patients having received a combined chemoradiotherapy following hysterectomy. In the group of 62 patients having that received radiotherapy following hysterectomy, which included the chemoradiotherapy patients, a higher PSMD9 expression significantly increased the odds for a recurrence to 1.983-fold even after FDR correction (P=0.0304). In conclusion, PSMD9 was indicated to be overexpressed in tumor tissues and associated with tumor cell proliferation. Therefore, PSMD9 may be useful as a tumor marker. Furthermore, increased PSMD9 overexpression may be used to predict resistance against radiation.

Keywords: Proteasome 26S non-ATPase Subunit 9; cervical cancer; chemoradiotherapy; immunohistochemistry; radiotherapy.

Copyright: © Köster et al.

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48
Oncol Lett
. 2020 Jul;20(1):569-580. doi: 10.3892/ol.2020.11591. Epub 2020 May 6.
In vitro and in vivo Evaluation of the Safety and Efficacy of a Novel Liquid Fiducial Marker for Image-Guided Radiotherapy
Liang-Chao Sun 1 2, Yi Su 3, Xing-Chen Ding 2, Dong-Shui Xu 2, Cheng-Ming Li 2, Lu Wang 2, Wan-Long Li 2, Xin-Dong Sun 2, Jin-Ming Yu 2, Xue Meng 2
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PMID: 32565982 PMCID: PMC7286123 DOI: 10.3892/ol.2020.11591
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Abstract
The true extent of a tumor is difficult to visualize, during radiotherapy, using current modalities. In the present study, the safety and feasibility of a mixture of N-butyl cyanoacrylate and lipiodol (NBCA/Lip) was evaluated in order to investigate the optimal combination for application as a fiducial marker for radiotherapy. Four combinations of NBCA/Lip injection (1:1-0.1, 1:1-0.15, 1:3-0.1 and 1:3-0.15 ml) were injected into the subcutaneous tissue of BALB/c mice. The changes in gross histopathology, body weight, skin score, marker volume, neutrophil and macrophage counts were observed to analyze the effects of the different mixing ratios and injection volumes, in order to identify the best combination. Evaluation according to the International Organization for Standardization criteria was further conducted in order to test the biocompatibility of the mixture, including an acute systematic assay with mice, cytotoxicity with L929 fibroblasts and delayed-type hypersensitivity tests with guinea pigs and an intradermal test with rabbits. The results revealed that at the seventh week, 42 markers (42/48; 87.5%) were still visible using computed tomography (CT) imaging. No serious adverse effects were observed throughout the study period; however, the combination of 1:1-0.1 ml had the lowest body weight and worst skin score. A review of the histopathological reaction to NBCA/Lip revealed a combination of acute inflammation, chronic inflammation, granulation tissue, foreign-body reaction and fibrous capsule formation. The 1:1 NBCA combination ratio resulted in the most intense tissue repair reaction and a slower degradation rate of markers. In general, the combination of 1:3-0.15 ml had a better fusion with local tissue, maintained a stable imaging nodule on CT images for 7 weeks and the final biocompatibility test demonstrated its safety. Overall, the findings of the present study demonstrated NBCA/Lip as a safe and feasible fiducial marker, when using the 1:3-0.15 ml combination.

Keywords: biocompatibility; esophageal cancer; image-guided radiotherapy; liquid fiducial marker; n-butyl cyanoacrylate.

Copyright: © Sun et al.

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49
Oncol Lett
. 2020 Jul;20(1):561-568. doi: 10.3892/ol.2020.11601. Epub 2020 May 13.
Germline Mutations in MEN1 Are Associated With the Tumorigenesis of Pituitary Adenoma Associated With Meningioma
Haibo Zhu 1, Yazhou Miao 2, Yutao Shen 2, Jing Guo 2, Weiyan Xie 2, Sida Zhao 2, Wei Dong 2, Yazhuo Zhang 1 2 3 4, Chuzhong Li 1 2 3 4
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PMID: 32565981 PMCID: PMC7285847 DOI: 10.3892/ol.2020.11601
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Abstract
Pituitary adenoma and meningioma are two of the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease, the tumorigenesis of which remains unclear. Therefore, the aim of the present study was to investigate the tumorigenesis of PAM. A total of 8,197 patients with pituitary adenoma were analyzed. Furthermore, the clinical data of 57 patients with PAM were compared with patients with multiple endocrine neoplasia 1 (MEN-1) syndrome. Whole exome sequencing (WES) was performed on 23 samples from patients with PAM and the germline mutation was verified by Sanger sequencing. The age of tumor penetrance (age of patients at diagnosis) for PAM was significantly higher than that for patients with MEN-1. Compared with MEN-1 patients, there was a significant association between PAM and female sex (P=0.004). Clonal analysis and phylogenetic tree construction suggested that the pituitary adenoma and meningioma in PAM don't originate from a common progenitor. WES revealed that 5/23 PAM samples had the recurrent germline mutation MEN1 c.1523G>A; p.G508D, which may be a genetic risk factor for PAM. Compared with patients with sporadic pituitary adenoma, the difference was statistically significant (P=0.0004). Compared with wild-type MEN1, there was a significant association between the MEN1 mutation and recurrence of pituitary adenoma, young age and larger diameter of the meningioma. The present study indicated that germline mutations in MEN1 may be associated with the tumorigenesis of PAM.

Keywords: MEN1; PAM; germline mutation.

Copyright: © Zhu et al.

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50
Oncol Lett
. 2020 Jul;20(1):541-550. doi: 10.3892/ol.2020.11627. Epub 2020 May 14.
Clinicopathological and Mutational Differences Between Tumors With Multiple Metastases and Single Lung Metastasis in Colorectal Cancer
Yuka Yanai 1, Takuo Hayashi 1, Yoichi Akazawa 2, Noboru Yatagai 2, Sho Tsuyama 1, Takashi Yao 1, Tsuyoshi Saito 1 3
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PMID: 32565980 PMCID: PMC7285844 DOI: 10.3892/ol.2020.11627
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Abstract
Cancer metastasis, particularly multiple metastatic cancer, is a significant event that affects patient prognosis. However, single metastasis can be treated by partial resection, although the clinicopathological and molecular profile of single lung metastasis has not been thoroughly elucidated. The present study examined tumor heterogeneity by comparing the mutation status between primary colorectal cancer (CRC) and corresponding metastatic lesions to identify prognostic factors associated with single lung metastasis and multiple metastases. The present study enrolled 31 cases of CRC; 20 cases with multiple metastases and 11 cases with single lung metastasis. Clinicopathologically, all cases with multiple metastases were tubular adenocarcinoma, and 3/11 cases with single metastasis were mucinous adenocarcinoma originating from the left side, the remaining 8 cases were tubular adenocarcinoma from the left side. CRC cases with multiple metastases exhibited more frequent vascular invasion, but not lymphatic invasion, than those with single lung metastasis. Furthermore, CRC with multiple metastases was associated with strong tumor budding (P=0.04). Patients with CRC with multiple metastases had lower recurrence-free survival rates compared with those with single lung metastasis (P=0.02). However, there was no significant difference between these two groups in terms of overall survival rates. A next-generation sequencing cancer hotspot panel was used to analyze a heterochronous multiple metastases case, including brain metastasis. Sanger sequencing, immunohistochemistry and microsatellite instability were examined for all 31 cases to reveal the molecular features. KRAS and TP53 mutation signatures were largely preserved throughout the metastatic events. TP53/APC mutations and overexpression of p53 appeared to be associated with the presence of lymphovascular invasion and strong tumor budding, respectively, although these differences were not statistically significant. Early relapses in patients with CRC could be a sign for eventual multiple metastases, although these may not affect the overall survival of patients with CRC. Considerable mutational changes were seemingly rare during metastatic events in patients with CRC.

Keywords: APC; KRAS; TP53; colorectal cancer; lung metastasis; mutation.

Copyright: © Yanai et al.

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