Oncol Lett
. 2020 Jul;20(1):533-540. doi: 10.3892/ol.2020.11587. Epub 2020 May 6.
Selective Inhibition of HDAC6 Sensitizes Cutaneous T-cell Lymphoma to PI3K Inhibitors
Malgorzata Bobrowicz 1 2, Aleksander Slusarczyk 1, Joanna Domagala 1 3, Michal Dwojak 1 3, Desislava Ignatova 2, Yun-Tsan Chang 2, Christoph Iselin 2, Nina Miazek-Zapala 1, Katsiaryna Marhelava 3 4, Emmanuella Guenova 2 5, Magdalena Winiarska 1
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PMID: 32565979 PMCID: PMC7285804 DOI: 10.3892/ol.2020.11587
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Abstract
Histone deacetylase (HDAC) inhibitors, approved for the treatment of cutaneous T-cell lymphoma (CTCL), are non-selective agents associated with an unsatisfactory response and considerable side-effects. Targeting single HDAC isoforms is considered to provide novel therapeutic options. HDAC6 is overexpressed in primary samples from patients with CTCL and preclinical studies using transgenic mice that spontaneously develop a CTCL-like disease, have suggested that combinations including HDAC6 inhibitors may be successful in the treatment of CTCL. PI3K inhibition is currently being tested in clinical trials for CTCL with promising results. Since HDAC6 is known to diminish the activity of Akt via its deacetylation, the aim of the present study was to evaluate the therapeutic potential of selective HDAC6 inhibitors in combination with PI3K inhibitors in CTCL. Through the genetic and pharmacological inhibition of HDAC6, it was demonstrated that combining HDAC6 with PI3K inhibition may be an attractive therapeutic option for patients with CTCL.

Keywords: CTCL; HDAC6; PI3K; targeted therapy.

Copyright: © Bobrowicz et al.

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52
Oncol Lett
. 2020 Jul;20(1):525-532. doi: 10.3892/ol.2020.11586. Epub 2020 May 4.
The Age of Paraffin Block Influences Biomarker Levels in Archival Breast Cancer Samples
Hong Chen 1, Qing-Qing Fang 2, Bo Wang 3
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PMID: 32565978 PMCID: PMC7285835 DOI: 10.3892/ol.2020.11586
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Abstract
The present study aimed to investigate the influence of paraffin block age on biomarker levels in archival breast cancer samples. Tissue blocks from five different block age groups were assessed using immunohistochemistry and fluorescence in situ hybridization. The difference in Q scores for estrogen receptor and progesterone receptor expression levels between original tests and repeated tests were significant for core needle biopsies prepared 10 years ago. The signal intensities of human epidermal growth factor receptor 2 and the centromere of chromosome 17 decreased with the age of the paraffin block. Moreover, 6 samples exhibited a negative shift in progesterone receptor Q scores for core needle biopsy samples with a Q score of 2. In conclusion, the age of paraffin blocks had significant effects on the expression levels of estrogen and progesterone receptors in core needle biopsies prepared 10 years ago. The results showed that samples with an age >7 years were not suitable for fluorescence in situ hybridization and interpretation of progesterone receptor levels for repeated core needle biopsy samples with a Q score of 2 requires caution.

Keywords: estrogen receptor; human epidermal growth factor receptor 2; paraffin block; progesterone receptor.

Copyright: © Chen et al.

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53
Oncol Lett
. 2020 Jul;20(1):517-524. doi: 10.3892/ol.2020.11605. Epub 2020 May 13.
Analysis of Immune-Related Signatures of Colorectal Cancer Identifying Two Different Immune Phenotypes: Evidence for Immune Checkpoint Inhibitor Therapy
Gang Chen 1, Lin Wang 2, Tongwei Diao 1, Ying Chen 1, Chengbo Cao 1, Xindong Zhang 3
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PMID: 32565977 PMCID: PMC7285802 DOI: 10.3892/ol.2020.11605
Free PMC article
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of numerous types of cancer, including colorectal cancer (CRC). Patients with CRC and deficient mismatch repair or high microsatellite instability could benefit from ICI treatment, although the response rate of most patients is low. Therefore, the immune subtyping of patients with CRC is required in order to determine the subtypes suitable for ICI treatment. The present study used a cohort of patients with CRC from The Cancer Genome Atlas (TCGA) to perform molecular subtyping, with results validated in three CRC cohorts from the Gene Expression Omnibus. Non-negative matrix factorization was used to achieve consensus molecular subtyping. The tumor immune dysfunction and exclusion algorithm was used to predict potential ICI therapy responses and gene set enrichment analysis was performed to define different pathways associated with the immune response. Two distinct subtypes of CRC were finally identified in TCGA cohorts, which were characterized as significantly different prognostic subtypes (low-risk and high-risk subtypes). Higher expression of programmed death-ligand 1, higher proportion of tumor-infiltrating lymphocytes and tumor mutation burden were significantly enriched in the low-risk subtype. Further pathway analysis revealed that the low-risk subtype was associated with immune response activation and signaling pathways involved in 'antigen processing and presentation'. Three independent CRC cohorts were used to validate the above findings. In summary, two clinical CRC subtypes were identified, which are characterized by significantly different survival outcomes and immune infiltration patterns. The findings of the present study suggest that ICI treatment may be more effective in the low-risk CRC subtype.

Keywords: CRC; ICI response; ICI therapy; immune subtyping; prognosis.

Copyright: © Chen et al.

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54
Oncol Lett
. 2020 Jul;20(1):509-516. doi: 10.3892/ol.2020.11588. Epub 2020 May 6.
High KIAA1522 Expression Predicts a Poor Prognosis in Patients With Hepatocellular Carcinoma
Yongzheng Xu 1, Chuandong Sun 1, Bing Han 1, Yue Xi 1, Mao Zhang 1, Jing Yang 1, Zongkai Chen 1
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PMID: 32565976 PMCID: PMC7285928 DOI: 10.3892/ol.2020.11588
Free PMC article
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor associated with a poor prognosis, and the molecular mechanisms remain poorly understood. KIAA1522 expression is upregulated in various types of tumor tissue; however, its function remains unknown in HCC. Bioinformatics analysis was undertaken using Oncomine, OncoLnc and other databases, in order to determine KIAA1522 expression in HCC and to analyze its association with postoperative prognosis. Reverse transcription-quantitative PCR was performed to detect KIAA1522 mRNA expression in primary HCC and adjacent normal tissues, while KIAA1522 protein expression was assessed via immunohistochemical staining. KIAA1522 expression and clinicopathological characteristics of primary HCC were evaluated, and their association with patient prognosis was analyzed. The Oncomine database results indicated that KIAA1522 expression in HCC and normal liver tissues was significantly different. RT-qPCR analysis demonstrated that KIAA1522 mRNA expression was significantly higher in HCC tissues compared with that in adjacent normal tissues. Immunohistochemical analysis indicated that expression rate of KIAA1522 protein was significantly higher in primary HCC tissues compared with that in normal liver tissues. The OncoLnc database results demonstrated that KIAA1522 expression was significantly associated with short-term survival. Kaplan-Meier survival analysis indicated that high KIAA1522 protein expression was significantly associated with short-term survival for patients with HCC. Multivariate Cox regression analysis demonstrated that tumor size, Tumor-Node-Metastasis stage and high KIAA1522 protein expression were independent predictors of a poor prognosis in patients with primary HCC. Furthermore, high KIAA1522 expression was significantly associated with postoperative survival time in primary HCC, and thus may be a potential molecular marker for prognosis in patients with this cancer type.

Keywords: KIAA1522; bioinformatic analysis; hepatocellular carcinoma; multivariate Cox regression analysis; prognosis.

Copyright: © Xu et al.

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55
Oncol Lett
. 2020 Jul;20(1):501-508. doi: 10.3892/ol.2020.11584. Epub 2020 May 4.
Correlation Between Preoperatively Predicted and Postoperatively Observed Renal Function Using an Imaging-Based Approach: A Retrospective Cohort Study
Jingchao Liu 1, Chuanxin Tian 1, Zhaocun Zhang 1, Guanwen Zhou 1, Benkang Shi 1, Haifeng Zhao 1, Xianzhou Jiang 1
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PMID: 32565975 PMCID: PMC7285876 DOI: 10.3892/ol.2020.11584
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Abstract
The aim of the present study was to preoperatively predict renal function following partial nephrectomy (PN) using an imaging-based approach and to examine the correlation between preoperatively predicted and postoperatively observed renal function in the study cohort. A total of 128 consecutive patients who underwent PN between May 2015 and March 2018 and had available clinical data were included in this study. A hand-scripting method was used to estimate the defected volume (Vdef) from preoperative computerized tomography scans, whereas a cylindrical method was used to obtain preoperative renal volume (Vpre). The function index (FI) was proposed as a new term to estimate preserved parenchyma percentage following PN. The FI was defined as f=(Vpre-Vdef)/Vpre for the operated kidney and adjusted as FI=0.5 × (f + 1) for the bilateral kidneys. The estimated glomerular filtration rates (GFRs) before surgery, one day after surgery and ~12 months after surgery were calculated using the Modification of Diet in Renal Disease Study equation. The GFR rate after PN was predicted by multiplying the preoperative GFR by the FI. The predictive role of the FI was further tested using multiple linear regression and correlation analyses. The median FI in the present study was 94% for unilateral kidney surgery and adjusted to 97% for bilateral kidneys. Linear correlation analysis revealed that the predicted GFR significantly correlated with the observed immediate postoperative GFR (R2, 0.594) and observed late postoperative GFR (R2, 0.828). In multivariate regression analysis, preoperative GFR (P<0.01) and warm ischemic time (P<0.01) were identified as independent determinants of the immediate postoperative renal function, whereas only FI (P<0.01) and preoperative GFR (P<0.01) were identified as independent determinants of late renal function after PN. The preoperatively predicted renal function using an imaging-based approach had a significant positive correlation with the postoperatively observed renal function. The FI estimated from the preoperative diagnostic images in the present study was identified as an independent determinant of long-term renal function after PN.

Keywords: CT; GFR; PN; warm ischemia.

Copyright: © Liu et al.

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56
Oncol Lett
. 2020 Jul;20(1):495-500. doi: 10.3892/ol.2020.11578. Epub 2020 Apr 28.
Downregulation of lncRNA PMS2L2 in Patients With Gastric Adenocarcinoma Predicts Poor Prognosis
Junping Bian 1, Guangchun Li 1, Zhen Zhang 1, Bin Liu 1
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PMID: 32565974 PMCID: PMC7285845 DOI: 10.3892/ol.2020.11578
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Abstract
Long non-coding RNA PMS1 homolog 2 mismatch repair system component pseudogene 2 (PMS2L2) is a key player in lipopolysaccharide-induced inflammatory responses. Preliminary deep sequencing data revealed that PMS2L2 was downregulated in gastric adenocarcinoma (GA) tissues compared with healthy adjacent tissues and the aim of the present study was to investigate the role of PMS2L2 in GA. In the present study, reverse transcription-quantitative PCR assays were performed to analyze gene expression. Cell transfections were performed to analyze gene interactions and Transwell assays were performed to analyze cell invasion and migration. The results revealed that PMS2L2 expression was downregulated in cancer tissues obtained from patients with GA compared with healthy adjacent tissues and was not significantly affected by clinical stage. Furthermore, low levels of PMS2L2 in cancer tissues were closely associated with a low overall 5-year survival rate in patients. MicroRNA (miR)-25 was upregulated in GA tissues compared with healthy adjacent tissues and inversely associated with PMS2L2 levels. In GA cells in vitro, overexpression of PMS2L2 downregulated the expression of miR-25, while miR-25 overexpression did not significantly affect PMS2L2 expression. Furthermore, PMS2L2 overexpression inhibited the migration and invasion of GA cells. miR-25 overexpression partially rescued the decreased migration and invasion of GA cells caused by PMS2L2 overexpression. Therefore, PMS2L2 may downregulate miR-25 expression to inhibit GA.

Keywords: gastric adenocarcinoma; long non-coding RNA PMS1 homolog 2 mismatch repair system component pseudogene 2; microRNA-25; prognosis.

Copyright: © Bian et al.

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57
Oncol Lett
. 2020 Jul;20(1):483-494. doi: 10.3892/ol.2020.11600. Epub 2020 May 13.
Identification of Key Genes Associated With the Progression of Intrahepatic Cholangiocarcinoma Using Weighted Gene Co-Expression Network Analysis
Zi Ye 1 2, Zhirui Zeng 3 4, Da Wang 5, Shan Lei 3 4, Yiyi Shen 6, Zubing Chen 1 2
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PMID: 32565973 PMCID: PMC7286119 DOI: 10.3892/ol.2020.11600
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Abstract
The present study aimed to identify the key genes that are associated with the progression of intrahepatic cholangiocarcinoma through weighted gene co-expression network analysis (WGCNA). A total of three gene datasets were downloaded from the Gene Expression Omnibus database, including GSE107943, GSE119336 and GSE26566. Differentially expressed genes (DEGs) between intrahepatic cholangiocarcinoma tissues and adjacent liver tissues were identified using GSE107943, while tissue specific genes between bile duct and liver tissues were identified using GSE26566. Following the removal of tissue-specific genes, real DEGs were used to construct the WGCNA to investigate the association between gene modules and clinical traits. Following functional analysis, pathway enrichment analysis and the construction of a protein-protein interaction (PPI) network were performed, hub genes were selected and their diagnostic value was verified in GSE119336 using a receiver operating characteristic curve. Finally, the protein levels of the hub genes were also verified in intrahepatic cholangiocarcinoma tissues. A total of 1,643 real DEGs were identified and used to construct the WGCNA. Additionally, a total of seven co-expressed gene modules were identified following WGCNA, while genes in brown and yellow modules were identified to be associated with multiple clinical traits (the number of clinical traits >3) and used as key modules. A total of 63 core key module genes were subsequently identified, and it was indicated that these genes were most enriched in the nucleus (Gene Ontology term) and the cell cycle pathway (Kyoto Encyclopedia of Genes and Genomes term). Finally, a total of eight genes, including cyclin B1, cell division cycle 20, cell division cycle associated 8, cyclin dependent kinase 1, centrosomal protein 55, kinesin family member 2C, DNA topoisomerase IIα and TPX2 microtubule nucleation factor, exhibited the highest score in PPI analysis and had a high diagnostic value for intrahepatic cholangiocarcinoma. In addition, the protein levels of these genes were also revealed to be increased in most intrahepatic cholangiocarcinoma tissues. These eight genes may be used as novel biomarkers for the diagnosis of intrahepatic cholangiocarcinoma.

Keywords: hub genes; intrahepatic cholangiocarcinoma; weighted gene co-expression network analysis.

Copyright: © Ye et al.

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58
Oncol Lett
. 2020 Jul;20(1):474-482. doi: 10.3892/ol.2020.11582. Epub 2020 May 4.
TGF-β1 Induces N-cadherin Expression by Upregulating Sox9 Expression and Promoting Its Nuclear Translocation in Human Oral Squamous Cell Carcinoma Cells
Taifu Hirano 1 2, Daishi Saito 2, Hiroyuki Yamada 2, Akira Ishisaki 1, Masaharu Kamo 1
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PMID: 32565972 PMCID: PMC7285821 DOI: 10.3892/ol.2020.11582
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Abstract
Squamous cell carcinoma (SCC) is the most frequent cancer that develops in the oral cavity. Epithelial-mesenchymal transition (EMT) is known to play an important role in the process of metastasis of SCC cells. In our previous study, we demonstrated that TGF-β1 induced EMT in the human oral SCC (hOSCC) cell line HSC-4. We also found that Slug plays an important role in suppressing E-cadherin expression and promotion of the migratory activity of HSC-4 cells. However, we also demonstrated that Slug does not participate in upregulation of N-cadherin expression, suggesting that EMT-related transcription factors other than Slug also play an important role in the process. In the present study, we aimed to elucidate how the transcription factor Sox9 affects the TGF-β1-induced upregulation of N-cadherin expression in HSC-4 cells. We found that TGF-β1 upregulated Sox9 expression in HSC-4 cells. In addition, Sox9 siRNA significantly abrogated the TGF-β1-induced upregulation of N-cadherin expression and inhibited the TGF-β1-promoted migratory activity in HSC-4 cells. We also demonstrated that TGF-β1 upregulated the phosphorylation status of Sox9 and then promoted nuclear translocation of Sox9 from the cytoplasm, possibly resulting in an increase in N-cadherin expression. The cyclic AMP-dependent protein kinase A inhibitor H-89, which is known to suppress phosphorylation of Sox9, significantly abrogated the TGF-β1-induced upregulation of N-cadherin expression. These results suggested that TGF-β1 induced N-cadherin expression by upregulating Sox9 expression and promoting its nuclear translocation, which results in EMT progression in hOSCC cells.

Keywords: EMT; N-cadherin; Sox9; TGF-β; squamous cell carcinoma.

Copyright: © Hirano et al.

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59
Review Oncol Lett
. 2020 Jul;20(1):465-473. doi: 10.3892/ol.2020.11623. Epub 2020 May 14.
Circular RNAs in Gastric Cancer: Biomarkers for Early Diagnosis
Chun-Mei Yang 1 2, Guang-Lei Qiao 1, Li-Na Song 1, Shisan Bao 1 3, Li-Jun Ma 1
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PMID: 32565971 PMCID: PMC7285985 DOI: 10.3892/ol.2020.11623
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Abstract
Circular RNAs (circRNAs) are highly conserved and stable closed-loop non-coding RNAs. They are involved in numerous biological functions, including regulating gene transcription or protein translation by interacting with proteins and regulating expression of microRNAs. The aberrant expression of circRNAs has been reported in many cancers, including gastric cancer. By regulating gene expression, circRNAs are able to affect the proliferation, invasion and metastasis of gastric cancer. The current review focused on the characteristics and biological functions of circRNAs, the carcinogenic potential and the possible implications of circRNAs on the diagnosis and treatment of gastric cancer. In conclusion, circRNAs may serve as potential biomarkers for diagnosis, as well as therapeutic targets.

Keywords: circular RNAs; gastric cancer; novel biomarkers.

Copyright: © Yang et al.

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60
Review Oncol Lett
. 2020 Jul;20(1):455-464. doi: 10.3892/ol.2020.11614. Epub 2020 May 13.
Signal Transducer and Activator of Transcription 6 as a Target in Colon Cancer Therapy
Yael Delgado-Ramirez 1, Vaneesa Colly 1 2, Giovanni Villanueva Gonzalez 2, Sonia Leon-Cabrera 1 2
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PMID: 32565970 PMCID: PMC7285805 DOI: 10.3892/ol.2020.11614
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Abstract
Signal transducer and activator of transcription 6 (STAT6) is a member of the STAT family of proteins that serve key roles in the initiation of tumorigenesis and malignant transformation. STAT6 is highly expressed in several types of cancer, including breast, pancreatic, prostate and colorectal cancer. STAT6 transduces signals in response to the binding of interleukin (IL)-4 and IL-13 to their receptors and regulates the expression of genes involved in the immune response, cell survival, tumor proliferation and metastasis. Patients with colorectal cancer exhibit high STAT6 activity in the colonic epithelium, and STAT6 expression is associated with lower survival rates, lymph node metastasis, changes in the epithelial barrier function and alterations in the inflammatory response. A number of studies investigating experimental models and cancer cell lines have revealed that STAT6 is associated with tumor growth and development, as well as with increased invasion and metastasis, suggesting that STAT6 inhibition may serve as a novel therapeutic strategy in colon cancer. The present review summarizes the evidence with regard to the implications of STAT6 in cancer biology and the direct and indirect effects on colon tumor transformation. Furthermore, the current treatment strategies targeting the IL-4/IL-13/STAT6 axis in colon cancer are discussed.

Keywords: colon cancer; interleukin-13; interleukin-4; signal transducer and activator of transcription 6; signaling; targeted therapy.

Copyright: © Delgado-Ramirez et al.

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61
Review Oncol Lett
. 2020 Jul;20(1):448-454. doi: 10.3892/ol.2020.11583. Epub 2020 May 4.
Pathogenesis of Pediatric B-cell Acute Lymphoblastic Leukemia: Molecular Pathways and Disease Treatments
Fang-Liang Huang 1 2, En-Chih Liao 3, Chia-Ling Li 1, Chung-Yang Yen 4, Sheng-Jie Yu 5
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PMID: 32565969 PMCID: PMC7285861 DOI: 10.3892/ol.2020.11583
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Abstract
B-cell acute lymphoblastic lymphoma (B-ALL) is a disease found mainly in children and in young adults. B-ALL is characterized by the rapid proliferation of poorly differentiated lymphoid progenitor cells inside the bone marrow. In the United States, ~4,000 of these patients are diagnosed each year, accounting for ~30% of childhood cancer types. The tumorigenesis of the disease involves a number of abnormal gene expressions (including TEL-AML1, BCR-ABL-1, RAS and PI3K) leading to dysregulated cell cycle. Risk factors of B-ALL are the history of parvovirus B 19 infection, high birth weight and exposure to environmental toxins. These risk factors can induce abnormal DNA methylation and DNA damages. Treatment procedures are divided into three phases: Induction, consolidation and maintenance. The goal of treatment is complete remission without relapses. Apart from traditional treatments, newly developed approaches include gene targeting therapy, with the aim of wiping out leukemic cells through the inhibition of mitogen-activated protein kinases and via c-Myb inhibition enhancing sensitivity to chemotherapy. To evaluate the efficacy of ongoing treatments, several indicators are currently used. The indicators include the expression levels of microRNAs (miRs) miR-146a, miR-155, miR-181a and miR-195, and soluble interleukin 2 receptor. Multiple drug resistance and levels of glutathione reductase can affect treatment efficacy through the increased efflux of anti-cancer drugs and weakening the effect of chemotherapy through the reduction of intracellular reactive oxygen species. The present review appraised recent studies on B-ALL regarding its pathogenesis, risk factors, treatments, treatment evaluation and causes of disease relapse. Understanding the mechanisms of B-ALL initiation and causes of treatment failure can help physicians improve disease management and reduce relapses.

Keywords: acute lymphoblastic leukemia; evaluation of treatment efficacy; pathogenesis of leukemia; risk factor; treatment of ALL.

Copyright: © Huang et al.

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62
Review Oncol Lett
. 2020 Jul;20(1):441-447. doi: 10.3892/ol.2020.11599. Epub 2020 May 8.
Oncology During the COVID-19 Pandemic: Challenges, Dilemmas and the Psychosocial Impact on Cancer Patients
Konstantinos Tsamakis 1 2, Maria Gavriatopoulou 3, Dimitrios Schizas 4, Athina Stravodimou 5, Aikaterini Mougkou 6, Dimitrios Tsiptsios 7, Vasileios Sioulas 8, Eleftherios Spartalis 9, Athanasios D Sioulas 10, Charalampos Tsamakis 11, Nikolaos Charalampakis 12, Christoph Mueller 2 13, Donna Arya 14, Paul Zarogoulidis 15, Demetrios A Spandidos 16, Meletios A Dimopoulos 17, Charalabos Papageorgiou 18, Emmanouil Rizos 1
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PMID: 32565968 PMCID: PMC7285823 DOI: 10.3892/ol.2020.11599
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Abstract
COVID-19 has caused unprecedented societal turmoil, triggering a rapid, still ongoing, transformation of healthcare provision on a global level. In this new landscape, it is highly important to acknowledge the challenges this pandemic poses on the care of the particularly vulnerable cancer patients and the subsequent psychosocial impact on them. We have outlined our clinical experience in managing patients with gastrointestinal, hematological, gynaecological, dermatological, neurological, thyroid, lung and paediatric cancers in the COVID-19 era and have reviewed the emerging literature around barriers to care of oncology patients and how this crisis affects them. Moreover, evolving treatment strategies and novel ways of addressing the needs of oncology patients in the new context of the pandemic are discussed.

Keywords: COVID-19; SARS-Cov-2; cancer; care; challenges; oncology; pandemic; patients; psychosocial impact; telemedicine.

Copyright: © Tsamakis et al.

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63
Oncol Lett
. 2020 Jul;20(1):420-430. doi: 10.3892/ol.2020.11562. Epub 2020 Apr 21.
Chemoresistance-associated Alternative Splicing Signatures in Serous Ovarian Cancer
Tianshui Sun 1, Qing Yang 1
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PMID: 32565967 PMCID: PMC7285883 DOI: 10.3892/ol.2020.11562
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Abstract
Primary platinum-based chemoresistance occurs in ~30% of patients with serous ovarian cancer. Chemoresistance is the main cause of disease recurrence, and accurate predictors to identify these patients with chemoresistance are required. Alternative splicing (AS) is a post-transcriptional modification process that is altered in cancer. A possible association between AS and chemoresistance is unclear and needs to be studied comprehensively in ovarian cancer. In the present study, RNA-sequencing data and clinical information for 320 patients with ovarian serous cystadenocarcinoma (OV) were downloaded from The Cancer Genome Atlas (TCGA) database. Splicing events were determined using the TCGA SpliceSeq tool. Seven types of AS events were identified. Univariate and multivariate logistic analyses were performed, and predictive models for OV chemoresistance were established, as well as a splicing network. A total of 22,036 AS events were identified in 7,404 genes, with 915 AS events detected in 677 genes that were significantly associated with chemoresistance in patients with OV. A receiver operating characteristic (ROC) curve was constructed for resistance predictive models composed of the most significant AS events. The area under the ROC curve was 0.931, indicating strong and efficient prediction of chemoresistance. Additionally, the high-risk score was associated with shorter overall survival. The splicing correlation network suggested a potential role of splicing factors in chemoresistance. In summary, the present study created a powerful predictor for primary platinum-based chemoresistance in patients with OV, identified splicing networks that could be involved in potential mechanisms of chemoresistance and provided potential targets to overcome chemoresistance.

Keywords: The Cancer Genome Atlas; alternative splicing; chemotherapy resistance; ovarian cancer; splicing factor.

Copyright © 2020, Spandidos Publications.

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64
Oncol Lett
. 2020 Jul;20(1):409-419. doi: 10.3892/ol.2020.11563. Epub 2020 Apr 21.
Role of Lymph Node Dissection in Radical Cystectomy
Keyi Wang 1, Heng Shi 1 2, Weipu Mao 1, Lei Yin 1, Guangchun Wang 1, Donglai Fan 1, Jinbo Xie 1, Weiyi Li 1, Bo Peng 1 3
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PMID: 32565966 PMCID: PMC7285989 DOI: 10.3892/ol.2020.11563
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Abstract
The number of lymph node dissections (LNDs) is an independent factor influencing the survival time of patients with bladder cancer (BCa) after radical resection (RC). The present study aimed to investigate the association between the number of LNDs and the survival of patients with BCa at different stages and who underwent RC in the United States of America and China. Records from 17,730 American patients with BCa and 158 Chinese patients with BCa were collected from the Surveillance, Epidemiology and End Results (SEER) and the Shanghai Tenth People's Hospital (China) databases, respectively. Kaplan-Meier curve and χ2 test were used to determine the overall survival time (OS) of patients with BCa. Cox regression analysis was used to analyze the effects of LND number on OS. Overall, 13,421 (75.7%) patients were negative for lymph node metastasis (N0) and 4,309 (24.3%) were positive for lymph node metastasis (N+) among the 17,730 American patients with BCa. In the group of 158 Chinese patients, 125 (79.1%) were N0 and 33 (20.9%) were N+. In the American patients, the median number of dissected nodes was 11.0 [interquartile range (IQR)=3.0-21.0] for N0 patients and 14.0 (IQR=8.0-23.0) for N+ patients. The median number of LNDs was 5.0 (IQR=2.0-7.0) for Chinese N0 patients and 5.0 (IQR=1.5-10.5) for Chinese N+ patients. The number of LNDs may therefore be an independent factor associated with survival in patients who underwent RC. Furthermore, a higher number of LNDs was associated with longer OS in patients with BCa [American patients, ≥13 nodes vs. ≤5 nodes, hazard ratio (HR)=0.62, 95% confidence interval (CI)=0.59-0.65, P<0.001; Chinese patients, ≥5 nodes vs. ≤1 node, HR=0.27, 95% CI=0.12-0.62, P=0.002]. The number of LNDs in patients with BCa and N+ was higher compared with number of LNDs in patients with BCa and N0 who underwent RC. More extensive LND improved the OS in both the patients from USA and China. Increasing the number of LNDs may therefore be crucial when treating patients with BCa.

Keywords: Epidemiology and End Results; Surveillance; bladder cancer; lymph node dissection; overall survival; radical cystectomy.

Copyright: © Wang et al.

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65
Oncol Lett
. 2020 Jul;20(1):391-400. doi: 10.3892/ol.2020.11535. Epub 2020 Apr 15.
The Effect of TKI Therapy and Chemotherapy Treatment Delivery Sequence on Total Progression-Free Survival in Patients With Advanced EGFR-mutated NSCLC
Jie Han 1, Yan Xu 2, Yumei Zhou 3, Aiju Yang 4, Jianfeng Cui 5, Pengxiang Chen 6, Hongyu Zhao 1, Xingqin Zhou 1, Chaoyan Shen 1, Jinming Yu 7, Heng Lu 8
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PMID: 32565965 PMCID: PMC7285897 DOI: 10.3892/ol.2020.11535
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Abstract
The present study aimed to evaluate the total progression-free survival (PFS) time of the 1st-line chemotherapy (CHT)/2nd-line tyrosine kinase inhibitor (TKI) and 1st-line TKI/2nd-line CHT therapeutic regimens. Data from patients with non-small-cell lung cancer (NSCLC) harboring sensitizing epidermal growth factor receptor (EGFR) mutations, who had received both TKI and platinum CHT were retrieved from the Shandong Cancer Hospital (Jinan, China) database. A total of 89 patients were included, 50 of whom were treated with the 1st-line CHT/2nd-line TKI regimen and the remaining 39 patients underwent a 1st-line TKI/2nd-line CHT regimen. The differences in total PFS time between the two regimens were analyzed. The median total PFS time was 14.28 months with the 1st-line CHT/2nd-line TKI regimen and 17.77 months with the 1st-line TKI/2nd-line CHT regimen (adjusted hazard ratio, 0.96; 95% confidence interval (CI), 0.56-1.66; P=0.886). A significant difference in PFS time was revealed between the two strategies when comparing only the 1st-line or 2nd-line treatments (all P<0.001). The objective response rate (RR) was 52.0% for those treated with 1st-line CHT/2nd-line TKI and 38.5% for the reverse regimen. After adjusting for associated factors, the odds ratio for the RR was 2.77 (95% CI: 0.77-9.90; P=0.117). The current results revealed that there was no significant difference between the total PFS time of patients with NSCLC undergoing the 1st-line CHT/2nd-line TKI regimen compared with patients with NSCLC undergoing the 1st-line TKI/2nd-line CHT regimen.

Keywords: EGFR mutation; NSCLC; PFS; TKI; chemotherapy.

Copyright © 2020, Spandidos Publications.

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66
Oncol Lett
. 2020 Jul;20(1):382-390. doi: 10.3892/ol.2020.11552. Epub 2020 Apr 21.
Comprehensive Characterization of Driver Genes in Diffuse Large B Cell Lymphoma
Zheng Fan 1, Renzhi Pei 1, Keya Sha 1, Lieguang Chen 1, Tiantian Wang 1, Ying Lu 1
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PMID: 32565964 PMCID: PMC7285964 DOI: 10.3892/ol.2020.11552
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Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common hematological malignancy and is one of the most frequent non-Hodgkin lymphomas. Large-scale genomic studies have defined genetic drivers of DLBCL and their association with functional and clinical outcomes. However, the lymphomagenesis of DLBCL is yet to be fully understood. In the present study, four computational tools OncodriveFM, OncodriveCLUST, integrated Cancer Genome Score and Driver Genes and Pathways were used to detect driver genes and driver pathways involved in DLBCL. The aforementioned tools were also used to perform an integrative investigation of driver genes, including co-expression network, protein-protein interaction, copy number variation and survival analyses. The present study identified 208 driver genes and 31 driver pathways in DLBCL. IGLL5, MLL2, BTG2, B2M, PIM1, CARD11 were the top five frequently mutated genes in DLBCL. NOTCH3, LAMC1, COL4A1, PDGFRB and KDR were the 5 hub genes in the blue module that were associated with patient age. TP53, MYC, EGFR, PTEN, IL6, STAT3, MAPK8, TNF and CDH1 were at the core of the protein-protein interaction network. PRDM1, CDKN2A, CDKN2B, TNFAIP3, RSPO3 were the top five frequently deleted driver genes in DLBCL, while ACTB, BTG2, PLET1, CARD11, DIXDC1 were the top five frequently amplified driver genes in DLBCL. High EIF3B, MLH1, PPP1CA and RECQL4 expression was associated with decreased overall survival rate of patients with DLBCL. High XPO1 and LYN expression were associated with increased overall survival rate of patients with DLBCL. The present study improves the understanding of the biological processes and pathways involved in lymphomagenesis. The driver genes, EIF3B, MLH1, PPP1CA, RECQL4, XPO1 and LYN, pave the way for developing prognostic biomarkers and new therapeutic strategies for DLBCL.

Keywords: CNV; PPI network; WGCNA; diffuse large B cell lymphoma; driver gene; driver pathway; overall survival rate.

Copyright: © Fan et al.

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67
Oncol Lett
. 2020 Jul;20(1):373-381. doi: 10.3892/ol.2020.11557. Epub 2020 Apr 21.
Claudin 10 Acts as a Novel Biomarker for the Prognosis of Patients With Ovarian Cancer
Zhongjun Li 1 2, Wenting Xuan 1, Lishan Huang 1, Niankun Chen 1 2, Zhiyong Hou 1, Biyan Lu 3, Chuangyu Wen 1, Suran Huang 1
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PMID: 32565963 PMCID: PMC7285858 DOI: 10.3892/ol.2020.11557
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Abstract
Ovarian cancer (OC) is one of the most fatal gynecological malignancies in the world and confers a poor 5-year survival rate. The present study was designed to discover novel prognostic markers for patients with OC in order to estimate disease metastasis or recurrence. Based on the large cohorts of transcriptome data from multicenter sources, a comprehensive analysis was performed to explore potential prognostic markers. A total of 269 differentially expressed genes were identified, of which 32 were upregulated and 237 downregulated in OC tissues compared with the corresponding expression in normal tissues. Kaplan-Meier analysis, log-rank test and nomogram analysis were employed to demonstrate that low expression levels of claudin 10 (CLDN10) were associated with a less favorable disease prognosis. The most promising prognostic marker for OC was subsequently selected. Additionally, the prognostic nomogram was constructed in order to assess the 5-year survival rate using CLDN10 expression as a prognostic marker for OC. Furthermore, gene set enrichment analysis and analysis of the tumor-associated competing endogenous RNA network were performed to elucidate the potential biological processes associated with CLDN10 expression. The current results indicated that CLDN10 may influence OC progression via transforming growth factor-β (TGF-β)- or WNT/β-catenin-induced epithelial-to-mesenchymal transition (EMT). The associations among CLDN10, microRNA-486-5p, TGF-β, WNT/β-catenin and EMT should be further investigated in future studies.

Keywords: claudin 10; competing endogenous RNA; ovarian cancer; prognosis; signaling pathways.

Copyright: © Li et al.

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68
Oncol Lett
. 2020 Jul;20(1):364-372. doi: 10.3892/ol.2020.11549. Epub 2020 Apr 21.
Serum Concentration of Sex Hormone-Binding Globulin in Healthy Volunteers and Patients With Breast Cancer Stratified by Sex and Age
Se Jung Park 1, Tae Soo Kim 1, Kyu Hyun Park 1, Woo Sun Kwon 1, Jin Ju Kim 2
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PMID: 32565962 PMCID: PMC7285803 DOI: 10.3892/ol.2020.11549
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Abstract
The objective of the present study was to compare sex hormone-binding globulin (SHBG) levels according to sex (healthy male and female volunteers) and age to determine reference values. Serum SHBG expression levels in patients with breast cancer with different tumor burden states were also determined. A total of 109 samples were obtained from 34 patients in 3 different disease states (non-tumor, localized tumor and systemic metastasis) during follow-up. A sandwich ELISA was conducted to measure SHBG, cancer antigen (CA)15-3 and CA125 expression levels. Wilcoxon rank-sum tests were performed on non-normally distributed data and an unpaired t-test was used for normally distributed variables. SHBG expression levels were higher in females compared with males (P<0.0001). When SHBG expression levels were compared by sex, the difference was maintained in the age groups <30, 30-39 and ≥50 years, but not in the 40-49 years group. In males, SHBG expression levels increased until the age of 49 and then decreased (P=0.01). In females, SHBG expression levels exhibited a decreased trend until the age of 49 (P=0.66). In patients with breast cancer, the SHBG expression levels revealed a decreasing trend after the age of 50, which was different compared with the healthy females. There was a decreasing trend of SHBG expression levels from pre-menopause to post-menopause healthy volunteers (P=0.74). CA15-3 (r2=0.07; P=0.59) and CA 125 (r2=-0.18; P=0.17) levels did not exhibit any significant correlation with SHBG expression levels. There was a significant difference in the SHBG expression levels between male and female healthy volunteers. SHBG expression levels also revealed different patterns between healthy female volunteers and female patients with breast cancer ≥50 years of age. The present study demonstrated that SHBG does not have value as a biomarker, but different reference values according to age and sex may aid in predicting high-risk groups for hormone-dependent cancer and guide treatment direction for post-menopausal breast cancer.

Keywords: breast cancer; healthy volunteers; reference value; sex hormone-binding globulin.

Copyright: © Park et al.

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69
Oncol Lett
. 2020 Jul;20(1):357-363. doi: 10.3892/ol.2020.11546. Epub 2020 Apr 16.
Inhibitory Effect of Dihydromyricetin on the Proliferation of JAR Cells and Its Mechanism of Action
Yanzhen Zuo 1, Yanjie Lu 2, Qian Xu 3, Dayong Sun 4, Xiujun Liang 3, Xiaoru Li 5, Yuhong Li 2
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PMID: 32565961 PMCID: PMC7286138 DOI: 10.3892/ol.2020.11546
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Abstract
Dihydromyricetin (DMY) is a novel natural drug with antitumor activity against some cancer cells without obvious toxicity. Previously, its apoptotic effect on human choriocarcinoma was detected. The present study further investigated the therapeutic potential of DMY as a new drug for the treatment of choriocarcinoma, as well as its anti-proliferative effect and mechanism of action. The short-term proliferation of JAR cells was determined by MTT assay, whereas the effect of DMY on long-term cell proliferation was determined by colony forming assay. Flow cytometry was used to detect changes in the cell cycle. Furthermore, western blotting was used to detect the expression levels of proliferation-associated proteins such as cyclin A1, cyclin D1, SMAD3 and SMAD4. Reverse transcription-quantitative PCR (RT-qPCR) was used to quantify mRNA expression levels. The results indicated that DMY inhibited short and long-term proliferation of JAR cells in a concentration-dependent manner. Flow cytometry demonstrated S/G2/M cell cycle arrest, and western blotting revealed the downregulation of SMAD3, SMAD4, cyclin A1 and cyclin D1 expression levels. The results of RT-qPCR and western blotting were consistent. Overall, the findings of the present study suggest that DMY inhibits the proliferation of human choriocarcinoma JAR cells, potentially through cell cycle arrest via the downregulation of cyclin A1, cyclin D1, SMAD3 and SMAD4 expression levels.

Keywords: JAR cells; cell cycle; choriocarcinoma; dihydromyricetin; proliferation.

Copyright: © Zuo et al.

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70
Oncol Lett
. 2020 Jul;20(1):337-345. doi: 10.3892/ol.2020.11545. Epub 2020 Apr 16.
Effects and Mechanism of the Bile Acid (Farnesoid X) Receptor on the Wnt/β-catenin Signaling Pathway in Colon Cancer
Jiayu Mao 1, Xueqi Chen 1, Chunsaier Wang 1, Wenbin Li 1, Jingnan Li 1 2
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PMID: 32565960 PMCID: PMC7285806 DOI: 10.3892/ol.2020.11545
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Abstract
The downregulation of farnesoid X receptor (FXR; gene name, nuclear receptor subfamily 1 group h member 4), an enteric nuclear bile acid receptor, has been reported in colorectal carcinoma (CRC), and FXR expression has been inversely correlated with CRC stage and clinical outcome. FXR knockdown in chronic colitis mouse models of intestinal tumorigenesis results in early mortality and increased tumor progression via promoting Wnt signaling. The aim of the present study was to explore the effects and mechanism of FXR on the Wnt/β-catenin signal pathway in CRC. FXR and β-catenin protein expression levels were detected in an ulcerative colitis mouse model and human colon cancer cell lines (HT-29, Caco-2 and HCT-116). Gain- and loss-of-function studies were conducted by transfecting colon cancer cells with FXR siRNA and treating them with the FXR agonist GW4064. Subsequently, β-catenin transcriptional activity was measured using the dual-luciferase assay, and β-catenin/TCF4 complex levels and β-catenin protein and mRNA expression levels were determined. FXR and β-catenin expression levels were inversely associated in both the animal model and colon cancer cells. The Wnt signaling pathway was activated by increased β-catenin/TCF4 complex levels upon FXR silencing; however, mRNA and protein levels of β-catenin were not significantly affected. The FXR agonist GW4064 significantly inhibited the proliferation of cells but promoted the transcriptional activity of β-catenin. Thus, the present study demonstrated that FXR influences the Wnt/β-catenin signaling pathway. Furthermore, loss of FXR expression promotes the transcriptional activity of β-catenin, whereas FXR activation results in the opposite effect.

Keywords: FXR; Wnt/β-catenin signaling pathway; colorectal neoplasms.

Copyright: © Mao et al.

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71
Oncol Lett
. 2020 Jul;20(1):326-336. doi: 10.3892/ol.2020.11548. Epub 2020 Apr 21.
Neuregulin 1 Enhances Cell Adhesion Molecule L1 Like Expression Levels and Promotes Malignancy in Human Glioma
Wen-Wen Lin 1, Guan-Yong Ou 1, Jia-Zhe Lin 2, San-Jun Yi 1, Wei-Cheng Yao 3, Hong-Chao Pan 1, Wei-Jiang Zhao 1 4
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PMID: 32565959 PMCID: PMC7285836 DOI: 10.3892/ol.2020.11548
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Abstract
Neural cell adhesion molecular L1-like protein (CHL1) is a member of the cell adhesion molecule L1 family and serves an important role in the development and progression of tumors. The cytokine neuregulin 1 (NRG1) has been indicated in the tumorigenesis and promotion of metastasis through the modulation of L1. However, the roles of NRG1 in regulating CHL1 in glioma have not been elucidated. The present study investigated the protein expression levels and roles of CHL1 and the possible correlation between NRG1 and CHL1 protein expression levels in human gliomas, both in vivo and in vitro. Using immunohistochemistry coupled with a human glioma tissue microarray, it was demonstrated that the percentage of CHL1-positive areas was the highest in grade II glioma tissues. Using immunofluorescence staining, a positive correlation was identified between the expression levels of CHL1 and proliferating cell nuclear antigen. In addition, CHL1 downregulation also resulted in increased senescence of U-87 MG human glioblastoma cells. In vitro, administration of NRG1α induced a significant increase in CHL1 protein expression levels in human glioma SHG-44 and U251 cells and in human glioblastoma U-87 MG cells, whereas NRG1β failed to increase CHL1 expression levels in U251 cells. These findings were further confirmed by the downregulation of NRG1 expression levels using small interfering RNA treatment, which resulted in the reduction of CHL1 protein expression levels in U-87 MG cells. These data indicate that NRG1 can regulate CHL1 protein expression levels in gliomas, that it is correlated with malignancy, and that NRG1 may contribute to malignancy by upregulating CHL1 protein expression levels in glioma/glioblastoma cells.

Keywords: cell adhesion molecule L1 like; glioblastoma; glioma; glioma cell line; neuregulin 1; tissue array.

Copyright: © Lin et al.

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72
Oncol Lett
. 2020 Jul;20(1):317-325. doi: 10.3892/ol.2020.11537. Epub 2020 Apr 15.
Significant Diagnostic Value of Circulating Tumour Cells in Colorectal Cancer
Haijiao Yu 1, Ling Ma 1, Yubing Zhu 1, Wenxia Li 1, Lei Ding 1, Hong Gao 1
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PMID: 32565958 PMCID: PMC7285991 DOI: 10.3892/ol.2020.11537
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Abstract
Circulating tumour cells (CTCs) have potential utility in various clinical applications for cancer management. The present study focused on evaluating the diagnostic role of CTCs in colorectal cancer (CRC). A total of 89 blood samples from 59 patients diagnosed with CRC and 30 healthy individuals were collected for CTC detection. The Cyttel method is an improved CTC detection strategy, which combines negative enrichment with immunofluorescence and fluorescence in situ hybridization. This method effectively detected a significant increase in total CTCs in patients with CRC (49/59) compared with those in healthy controls (3/30). A cut-off value of 2 CTCs/3.2 ml blood yielded a sensitivity of 83.05% and a specificity of 100%. Additionally, three traditional serum tumour markers, namely carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9) and CA72-4, were examined by immunoassays. The diagnostic sensitivity of CTCs was much higher than that of CEA, CA19-9 and CA72-4 alone or in combination, particularly in patients with early stage CRC. The combined sensitivity of CTCs and CEA reached 91.53%, which was only slightly lower than the sensitivity of all four markers combined (CTCs + CEA + CA19-9 + CA72-4). CTCs with aneuploidy of chromosome 7 or 8 were carefully distinguished, and the associations among different types of CTCs, clinicopathological characteristics and overall survival were statistically analysed. Total CTCs were revealed to be significantly associated with tumour differentiation and nerve invasion. CTCs were more likely to be detected in poorly differentiated CRC tumours than in well- and moderately-differentiated tumours (P=0.026). Furthermore, to the best of our knowledge, the present study was the first to report that CTCs with multiploidy of chromosome 7 were significantly associated with TNM stage. These CTCs exhibited a high chance of being identified in the peripheral blood of patients with late-stage CRC (stage III-IV; P=0.031). The present study suggests that the combination of CTCs and CEA may serve as an effective potential diagnostic and prognostic indicator in patients with CRC. Detection of CTCs with aneuploidy may have increased specificity in predicting highly malignant and invasive tumours in CRC management.

Keywords: Cyttel method; aneuploidy; circulating tumour cells; colorectal cancer; tumour markers.

Copyright: © Yu et al.

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73
Oncol Lett
. 2020 Jul;20(1):308-316. doi: 10.3892/ol.2020.11574. Epub 2020 Apr 24.
Prognostic and Predictive Value of immune/stromal-related Gene Biomarkers in Renal Cell Carcinoma
Sen Wang 1, Xiangguang Zheng 1, Xinglu Chen 1, Xiaojun Shi 2, Sansan Chen 1
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PMID: 32565957 PMCID: PMC7285855 DOI: 10.3892/ol.2020.11574
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Abstract
Immune/stromal-associated genes may be promising biomarkers for cancer diagnosis and the determination of clinical cancer treatment options. The aim of the present study was to identify prognostic stromal/immune-associated genes in renal cell carcinoma (RCC). RCC gene expression data (885 cases) were obtained from The Cancer Genome Atlas database. Immune/stromal scores were calculated by using the ESTIMATE package in R. Immune/stromal scores were significantly associated with Tumor-Node-Metastasis stage, clinical stage and overall survival rate (P<0.05). There were 419 differentially expressed genes (DEGs) based on immune scores and 738 DEGs based on stromal scores. Among these DEGs, 406 DEGs based on stromal scores and 252 DEGs based on immune scores were significantly associated with overall survival rate (P<0.05). The biological functions of these DEGs were primarily enriched in the 'immune response' and 'regulation of cell migration and proliferation'. These DEGs were observed in a protein-protein interaction network. A LASSO Cox regression model was used to build a prognostic 6 gene-based classifier, including the IL21R, ATP6V1C2, GBP1, P2RY10, GBP4 and TNNC2 genes [area under the curve (AUC) =0.776]. The predictive model which combined this classifier with clinical prognostic factors had a high accuracy in predicting patient survival in RCC (combined AUC =0.899). Taken together, these results demonstrated that there are significant associations between immune/stromal scores and clinicopathological staging. A set of tumor microenvironment-associated genes that have powerful prognostic value in patients with RCC were identified in the present study.

Keywords: gene biomarker; immune score; renal cell carcinoma; stromal score; tumor microenvironment.

Copyright: © Wang et al.

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74
Oncol Lett
. 2020 Jul;20(1):299-307. doi: 10.3892/ol.2020.11570. Epub 2020 Apr 23.
miR-208b-5p Inhibits Invasion of Non-Small Cell Lung Cancer Through the STAT3 Pathway by Targeting interleukin-9
Jun Ma 1, Hong-Feng Tong 2, Jie-Huan Lin 1, Fu-Nan Chen 1, Can-Xing Wu 1, Cheng-Zhang Cao 1, Jian Wu 1, Shu-Qiao Hu 1
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PMID: 32565956 PMCID: PMC7285925 DOI: 10.3892/ol.2020.11570
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Abstract
Previous studies reported a dysregulation of micro (mi)R-208b-5p expression level in various types of human cancer; however, the role of miR-208-5p in non-small cell lung cancer (NSCLC) remains unclear. Therefore, the present study aimed to determine whether miR-208b-5p could regulate NSCLC progression. A total of 62 pairs of primary tumor and adjacent normal tissues were collected from patients with NSCLC. miR-208b-5p expression level was determined by reverse transcription-quantitative polymerase chain reaction. Furthermore, miR-208b-5p mimics was transfected into NSCLC A549 and H1299 cells in order to upregulate miR-208b-5p expression. Dual-luciferase reporter assay was utilized to investigate the associations between miR-208b-5p and IL9 mRNA. The results demonstrated that miR-208b-5p expression decreased in NSCLC tissues and cell lines. Furthermore, miR-208b-5p overexpression inhibited A549 and H1299 cell proliferation and invasiveness. miR-208b-5p was demonstrated to bind directly to the 3' untranslated region of interleukin-9 (IL-9) and therefore decreased its expression. In the NSCLC-derived cell lines, miR-208b-5p inactivated IL-9/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Furthermore, enhanced IL-9 level decreased the miR-208b-5p-mediated suppression of epithelial-mesenchymal transition in NSCLC cells by inactivating the STAT3 signaling pathway. In conclusion, the findings from this study demonstrated that miR-208b-5p inhibited migration and invasion of NSCLC cells. The anti-tumor activity of miR-208b-5p may be mediated by IL-9 and STAT-3 pathway.

Keywords: interleukin-9; invasion; miR-208b-5p; non-small cell lung cancer; proliferation.

Copyright: © Ma et al.

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75
Oncol Lett
. 2020 Jul;20(1):292-298. doi: 10.3892/ol.2020.11572. Epub 2020 Apr 24.
Vitamin D3 Mediates miR-15a-5p Inhibition of Liver Cancer Cell Proliferation via Targeting E2F3
Yulong Li 1 2, Qiang Lin 1, Su'E Chang 3, Rong Zhang 1, Jingjie Wang 1
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PMID: 32565955 PMCID: PMC7285896 DOI: 10.3892/ol.2020.11572
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Abstract
Vitamin D3 has been demonstrated to suppress the development and progression of liver cancer, but the mechanism is unclear. The effects of vitamin D3 and microRNA (miR)-15a-5p on liver cancer cells were investigated in the present study using MTT and colony formation assays, flow cytometry, western blotting and reverse transcription-quantitative PCR. A dual-luciferase reporter assay was performed to determine whether E2F transcription factor 3 (E2F3) was a target of miR-15a-5p. The effects of silencing the E2F3 gene expression in liver cancer cells were investigated using a small interfering RNA. Vitamin D3 suppressed liver cancer cell proliferation, induced apoptosis and increased miR-15a-5p expression. Treatment with the miR-15a-5p mimics significantly suppressed liver cancer cell proliferation compared with that of the controls. Bioinformatics analysis and a dual-luciferase reporter assay demonstrated that E2F3 was a target of miR-15a-5p and that silencing E2F3 inhibited liver cancer cell proliferation. Therefore, Vitamin D3 suppressed cell proliferation by miR-15a-5p-mediated silencing of E2F3 gene expression. These findings suggested a role for vitamin D3 and E2F3 targeting as potential novel liver cancer therapies.

Keywords: E2F3; miR-15a-5p; proliferation; vitamin D3.

Copyright: © Li et al.

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76
Oncol Lett
. 2020 Jul;20(1):275-291. doi: 10.3892/ol.2020.11573. Epub 2020 Apr 24.
Distinct Diagnostic and Prognostic Values of γ-aminobutyric Acid Type A Receptor Family Genes in Patients With Colon Adenocarcinoma
Ling Yan 1, Yi-Zhen Gong 1, Meng-Nan Shao 2, Guo-Tian Ruan 1, Hai-Lun Xie 1, Xi-Wen Liao 3, Xiang-Kun Wang 3, Quan-Fa Han 3, Xin Zhou 3, Li-Cheng Zhu 4, Feng Gao 1, Jia-Liang Gan 1
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PMID: 32565954 PMCID: PMC7286117 DOI: 10.3892/ol.2020.11573
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Abstract
In the present study, the significance of GABAA genes in colon adenocarcinoma (COAD) were investigated from the view of diagnosis and prognosis. All data were achieved from The Cancer Genome Atlas. Overall survival was analyzed by the Kaplan-Meier analyses and Cox regression model and the hazard ratios and 95% confidence interval were calculated for computation. The Database for Annotation, Visualization and Integrated Discovery, and the Biological Networks Gene Ontology (BiNGO) softwares were applied to assess the biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway analysis to predict the biological function of GABAA genes. The associated Gene Ontology and KEGG pathways were conducted by Gene Set Enrichment Analysis (GSEA). From receiver operating characteristics curves analysis, it was found that the expression of GABR, γ-aminobutyric acid type A receptor GABRA2, GABRA3, GABRB2, GABRB3, GABRG2, GABRG3, GABRD, GABRE were correlated with COAD occurrence [P<0.0001, area under the curve (AUC)>0.7]. The low expression of the GABRB1, GABRD, GABRP and GABRQ in genes after tumor staging adjustment were positively correlated with the overall survival rate [P=0.049, hazard ratio (HR)=1.517, 95% confidence interval (CI)=1.001-2.297; P=0.006, HR=1.807, 95% CI=1.180-2.765; P=0.005, HR=1.833, 95% CI=1.196-2.810; P=0.034, HR=1.578, 95% CI=1.036-2.405). GSEA showed enrichment of cell matrix adhesion, integrin binding, angiogenesis, endothelial growth factor and endothelial migration regulation in patients with COAD with GABRD overexpression. GABRB1, GABRD, GABRP and GABRQ were associated with the prognostic factors of COAD. The expression levels of GABRA2, GABRA3, GABRB2, GABRB3, GABRG2, GABRD and GABRE may allow differentiation between tumor tissues and adjacent normal tissues.

Keywords: colon adenocarcinoma; diagnosis; mRNA; prognosis; γ-aminobutyric acid type A receptor.

Copyright: © Yan et al.

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77
Oncol Lett
. 2020 Jul;20(1):266-274. doi: 10.3892/ol.2020.11547. Epub 2020 Apr 21.
Hsa_circ_0038646 Promotes Cell Proliferation and Migration in Colorectal Cancer via miR-331-3p/GRIK3
Haipeng Du 1, Zhiguo He 1, Fumei Feng 1, Daming Chen 1, Lei Zhang 1, Jingzhen Bai 1, Huiguo Wu 1, Enkun Han 1, Jiansheng Zhang 1
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PMID: 32565953 PMCID: PMC7286133 DOI: 10.3892/ol.2020.11547
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Abstract
Increasing evidence supports the essential roles of circular RNAs (circRNAs) and microRNAs (miRNAs/miRs) in different types of human cancer. For example, hsa_circ_0137008 functions as a sponge for mi-338-5p and inhibits the malignant phenotype in colorectal cancer. Furthermore, hsa_circ_RNA_0011780 downregulates FBXW7 by targeting miR-554a and suppressing the progression of non-small cell lung cancer. Thus far, only a single report has identified that the miRNA miR-331-3p exerts a pivotal effect on human colorectal cancer (CRC) evolution. However, both the up- and downstream regulatory mechanisms of miR-331-3p are unclear. In the present study, it was predicted via bioinformatics analysis that the circRNA, hsa_circ_0038646, and the glutamate receptor ionotropic kainate 3 (GRIK3) gene contain binding sites that can interact with miR-331-3p. Thus, hsa_circ_0038646/miR-331-3p/GRIK3 may be a novel therapeutic pathway for CRC. Reverse transcription-quantitative PCR and western blotting analyses were performed, as well as cell proliferation, luciferase reporter and Transwell migration assays. Hsa_circ_0038646 was overexpressed in both CRC cells and tissues, and this aberrant expression was positively related with increasing tumor grade. Knockdown of hsa_circ_0038646 significantly weakened human CRC cell proliferation and migration. It was shown that hsa_circ_0038646 can sponge miR-331-3p to suppress its expression, and that suppression of miR-331-3p can reverse the effects of hsa_circ_0038646 inhibition in CRC cells. It was determined that GRIK3 is a downstream target of miR-331-3p, and that hsa_circ_0038646 could increase the levels of GRIK3 by suppressing miR-331-3p in CRC cells. Restoring GRIK3 expression rescued the weakened CRC cell proliferation and migration following hsa_circ_0038646 knockdown. The present study indicated that hsa_circ_0038646 functions as a tumor promoter in CRC by increasing GRIK3 expression via sponging of miR-331-3p. The hsa_circ_0038646/miR-331-3p/GRIK3 axis may be a novel therapeutic and diagnostic target of CRC.

Keywords: colorectal cancer; glutamate receptor ionotropic kainate 3; hsa_circ_0038646; microRNA-331-3p; migration; proliferation.

Copyright: © Du et al.

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78
Oncol Lett
. 2020 Jul;20(1):257-265. doi: 10.3892/ol.2020.11569. Epub 2020 Apr 23.
P4HB Modulates Epithelial-Mesenchymal Transition and the β-catenin/Snail Pathway Influencing Chemoresistance in Liver Cancer Cells
Xing Ma 1, Jiening Wang 2, Juhua Zhuang 1, Xiaokun Ma 1, Ni Zheng 1, Yanan Song 2, Wei Xia 1
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PMID: 32565952 PMCID: PMC7285890 DOI: 10.3892/ol.2020.11569
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Abstract
The aim of the present study was to investigate the role of prolyl 4-hydroxylase beta polypeptide (P4HB) in the chemoresistance of liver cancer. Drug-resistant liver cancer cell lines, such as HepG2/adriamycin (ADR) cells, were treated and screened using adriamycin. Gene interference was used to silence the expression of P4HB in liver cancer cells. Cell viability, invasiveness and migration were assessed using CCK8, Transwell and wound healing assays, respectively. In addition, changes to key genes and proteins in the epithelial-mesenchymal transition (EMT) and β-catenin/Snail pathway were analyzed using reverse transcription-quantitative PCR and western blotting. Drug-resistant HepG2/ADR cells were successfully cultivated; the IC50 to ADR for HepG2/ADR and HepG2 cell lines was 4.85 and 0.61 µM, respectively. HepG2/ADR cells exhibited higher invasion and migration abilities compared with HepG2 cells (P<0.05). E-cadherin mRNA and protein expression levels in HepG2/ADR cells were decreased significantly, whereas P4HB, N-cadherin and vimentin mRNA and protein levels were significantly increased compared with HepG2 cells (all P<0.05). Knockdown of P4HB significantly decreased cell viability and the invasion and migration ability of HepG2/ADR cells. In addition, P4HB knockdown enhanced E-cadherin mRNA and protein expression levels, whereas N-cadherin, vimentin, total β-catenin, nuclear β-catenin and Snail mRNA and protein levels were significantly decreased (all P<0.05). Overall, the present study demonstrated that EMT and β-catenin/Snail pathway influence P4HB modulation in liver cancer chemoresistance.

Keywords: P4HB; chemoresistance; epithelial-mesenchymal transition; liver cancer; β-catenin/Snail pathway.

Copyright: © Ma et al.

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79
Oncol Lett
. 2020 Jul;20(1):248-256. doi: 10.3892/ol.2020.11555. Epub 2020 Apr 21.
STAT1 Is a Modulator of the Expression of Frequently Rearranged in Advanced T-cell Lymphomas 1 Expression in U251 Cells
Geng Guo 1, Shule Wang 1, Yining Hao 1, Yeqing Ren 1, Yongqiang Wu 1, Jianping Zhang 1, Dong Liu 1
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PMID: 32565951 PMCID: PMC7285825 DOI: 10.3892/ol.2020.11555
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Abstract
Aberrant expression of frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) contributes to poor prognosis in a number of carcinomas. However, its role in glioma remains controversial. In the present study, gene expression profiling was performed using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) functional enrichment and ingenuity pathway analysis (IPA) to evaluate the differential expression of genes and proteins in FRAT1 knockdown U251 glioma cells in comparison with the control. Western blot analysis was conducted to assess the expression levels of FRAT1 and STAT1. A total of 895 downregulated genes were identified in FRAT1-silenced U251 cells. The most enriched processes determined by GO and KEGG analysis of the 895 differentially expressed genes were associated with proliferation, migration and invasion. According to IPA, significant canonical pathways, including the interferon, hepatic fibrosis and Wnt/β-catenin signaling pathways, were identified to be the major enriched pathways. The elevated expression of STAT1 in U251 cells was validated. These results highlighted the regulatory role of FRAT1 in glioma cells with upregulated STAT1 expression.

Keywords: U251 cells; frequently rearranged in advanced T cell lymphomas 1; pathway; signal transducer and activator of transcription 1.

Copyright: © Guo et al.

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80
Oncol Lett
. 2020 Jul;20(1):235-247. doi: 10.3892/ol.2020.11534. Epub 2020 Apr 15.
lncRNA-CD160 Decreases the Immunity of CD8 + T Cells Through Epigenetic Mechanisms in Hepatitis B Virus Infection
Jiansong Wu 1, Qiang Niu 1, Jie Yuan 1, Xiaodan Xu 1, Liuxia Cao 1
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PMID: 32565950 PMCID: PMC7286002 DOI: 10.3892/ol.2020.11534
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Abstract
The transfer and development of chronic hepatitis B virus (HBV) infection is associated with the T cell immune response, therefore investigating the key regulators of cell immune response is needed to improve chronic HBV treatment. Blood samples from patients with chronic HBV infection were used to confirm the correlation between HBV infection stage and CD160 receptor expression levels in CD8+ T cells, the CD8+ T cells are used to research the mechanism of T cell immune response modulation, moreover, C3H/HeN mice with reduced CD160 expression levels were used to investigate the association between long non-coding (lnc)RNA-CD160 and HBV infection. Long non-coding (lnc)RNA-CD160 and histone-modification enzyme gene histone deacetylase 11 (HDAC11) expression levels were negatively associated with CD160 expression. lncRNA-CD160 can inhibit the secretion of IFN-γ and TNF-α through HDAC11 recruitment and bind to HDAC11 to form a complex on the promoters of IFN-γ and TNF-α. The HDAC11, IFN-γ and TNF-α form a complex and enhance the methylation of H3K9Me1, chromatin changes into the heterochromatin and the transcription of IFN-γ and TNF-α is blocked; moreover, the HDAC11/IFN-γ/TNF-α complex can also inhibit the secretion of IFN-γ and TNF-α in CD160- CD8+ T cells and suppresses the function of CD8+ T cells. Furthermore, small interfering RNA targeting lncRNA-CD160 can block HBV infection progression. lncRNA-CD160 acts as an immune suppressive factor and is expressed at a high level in peripheral blood CD8+ T cells of HBV infected patients. Furthermore, high expression levels of lncRNA-CD160 can contribute to the inhibition of IFN-γ and TNF-α secretion in CD8+ T cells and decrease the immune response of CD8+ T cells. Therefore, lncRNA-CD160 may become a new target for immunotherapy of chronic HBV infection in the future and may provide a new therapeutic strategy for the treatment of HBV infection.

Keywords: CD160; T cells; hepatitis B virus; immune responses; long non-coding RNA.

Copyright: © Wu et al.

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81
Oncol Lett
. 2020 Jul;20(1):226-234. doi: 10.3892/ol.2020.11561. Epub 2020 Apr 21.
Expression and Regulation Effects of Chemokine Receptor 7 in Colon Cancer Cells
Xiang Li 1, Xuemei Wang 1, Zitao Li 2, Yanjun Liu 1, Liang Sang 1, Zhen Zhang 1, Yixia Zhang 1
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PMID: 32565949 PMCID: PMC7285870 DOI: 10.3892/ol.2020.11561
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Abstract
In China the incidence and mortality rates of colon cancer have been increasing annually. Studies have revealed that CXCR7 is expressed in many tumors. The aim of the present study was to investigate the function of CXCR7 in colon cancer. The expression level of chemokine receptor 7 (CXCR7) in Caco-2 and HCT116 cells was investigated to elucidate the effect of CXCR7 on cell biological behavior. Reverse transcription-quantitative PCR and western blot analysis were used to detect the expression level of CXCR7 in Caco-2 and HCT116 cells after transfection with small interfering (si)RNA. To analyze the in vitro biological function of CXCR7, cell proliferation was measured using a Cell Counting Kit-8 assay, and cell invasion and migration were measured using Matrigel, and Transwell and wound healing assays. siRNAs were successfully transfected into Caco-2 and HCT116 cells and resulted in a decrease in CXCR7 protein and mRNA expression. Downregulation of CXCR7 inhibited Caco-2 and HCT116 cell proliferation, invasion, and migration. Regulation of CXCR7 expression may affect the biological behavior of Caco-2 and HCT116 cells, suggesting that CXCR7 has a potential role in molecular therapy in colon cancer.

Keywords: CXCR7; biological behaviors of neoplasms; colon; gene expression.

Copyright: © Li et al.

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82
Oncol Lett
. 2020 Jul;20(1):209-214. doi: 10.3892/ol.2020.11559. Epub 2020 Apr 21.
Epidural Angiolipoma With Concomitant Intradural Extramedullary Capillary Hemangioma at the Same Spinal Level: A Case Report
Yongquan Cheng 1, Kaiwu Lu 1, Hui Jiang 1
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PMID: 32565948 PMCID: PMC7286118 DOI: 10.3892/ol.2020.11559
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Abstract
Spinal epidural angiolipomas (SALs) and spinal intradural extramedullary capillary hemangiomas (SIECHs) are both types of rare benign tumor, and their pathogeneses appear to be associated. The present report is, to the best of our knowledge, the first case of spinal angiolipoma and intradural extramedullary capillary hemangioma occurring at the same spinal level. A 54 year-old male patient experienced two operations within four months due to the occurrence of SAL and one SIECH at the T3 level presenting with sudden paraplegia. Although the co-occurrence of SAL and SIECH at the same spinal level is an extremely rare condition, omitting the intradural tumor may be averted via scrutiny of preoperative images.

Keywords: clinical presentations; diagnosis; spinal angiolipomas; spinal intradural extramedullary capillary hemangiomas; treatment.

Copyright: © Cheng et al.

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83
Oncol Lett
. 2020 Jul;20(1):201-208. doi: 10.3892/ol.2020.11571. Epub 2020 Apr 23.
PKUTHLP Score: A Comprehensive System to Predict Surgical Approach in Radical Nephrectomy and Thrombectomy
Xun Zhao 1, Zhuo Liu 1, Hongxian Zhang 1, Liwei Li 2, Shiying Tang 1, Guoliang Wang 1, Shudong Zhang 1, Shumin Wang 2, Xiaojun Tian 1, Lulin Ma 1
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PMID: 32565947 PMCID: PMC7285736 DOI: 10.3892/ol.2020.11571
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Abstract
The present study aimed to develop an accurate preoperative scoring system to predict the probability of using laparoscopic surgery in radical nephrectomy and thrombectomy. The clinical data of 123 patients with renal cell carcinoma with renal vein or inferior vena cava tumour thrombus admitted to the Department of Urology at Peking University Third Hospital between January 2015 and May 2018 were retrospectively analysed. Univariate and multivariate regression analyses were used to create the scoring system with an emphasis on the area improvement under the receiver operating characteristic curve. A total of 58 (47.2%) patients underwent complete laparoscopic surgery, 56 (45.5%) underwent complete open surgery and 9 (7.3%) underwent laparoscopic conversion to open surgery. The final multivariable model included the following three factors: Clinical node stage (P=0.030), Mayo classification (P<0.001) and tumour diameter (P=0.001). These three variables were then used to construct the score system named Peking University Third Hospital Laparoscopic Probability (PKUTHLP), which ranges from 0-5. The proportion of patients undergoing laparoscopic surgery for each level of the PKUTHLP score were as follows: 0 (n=20), 100%; 1 (n=34), 67.6%; 2 (n=21), 33.3%; 3 (n=21), 19.0%; 4 (n=23), 17.4%; and 5 (n=4), 0.0%. Overall, the PKUTHLP score accurately predicted the probability of using laparoscopic surgery in radical nephrectomy and thrombectomy; however, prospective validation of the PKUTHLP scoring system is required.

Keywords: laparoscopic surgery; renal cell carcinoma; surgical approach; tumour thrombus.

Copyright: © Zhao et al.

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84
Oncol Lett
. 2020 Jul;20(1):183-192. doi: 10.3892/ol.2020.11550. Epub 2020 Apr 21.
Efficacy and Safety of CT-guided 125 I Brachytherapy in Elderly Patients With Non-Small Cell Lung Cancer
Jing Zhao 1, Zheng Zhi 2, Hongtao Zhang 1, Jinxin Zhao 1, Yan Di 1, Ke Xu 1, Chunling Ma 1, Zezhou Liu 1, Aixia Sui 1, Juan Wang 1
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PMID: 32565946 PMCID: PMC7286004 DOI: 10.3892/ol.2020.11550
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Abstract
Non-small cell lung cancer (NSCLC) has become the most common cancer type and the leading cause of cancer-associated mortality worldwide. The aim of the present retrospective study was to evaluate the efficacy and safety of computed tomography (CT)-guided 125I brachytherapy alone in elderly patients with NSCLC. A total of 26 elderly patients with NSCLC stage I-III who had an inoperable lesion or progressive disease following radio-chemotherapy were treated with CT-guided 125I seed implantation for lung lesions and included in the present study. The prescribed dose of 125I brachytherapy was 80-140 Gy, and dosimetric verification was performed immediately after the procedure. The response rate (RR) and local control rate (LCR) were analyzed according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Survival was estimated using the Kaplan-Meier method. Safety and complications were also documented. All patients were aged 65-85 years (median age, 77 years) and successfully completed the procedure, and the median follow-up time was 9.4 months (range, 3-31 months). After a 6-month follow-up, for pulmonary lesions, complete response (CR) was achieved in 11 (42.3%) cases, partial response in 9 (34.6%) cases, stable disease in 4 (15.4%) cases and progressive disease in 2 (7.7%) cases. The 6-month RR and LCR were 76.9 (20/26) and 92.3% (24/26), respectively. The mean overall survival (OS) time was 11.7±7.6 months and the 0.5- and 1-year OS rates were 90.1 and 73.3%, respectively. Tumor-related symptoms in patients were significantly alleviated following the procedure. No severe complications occurred during and after the procedure of 125I seed implantation. In conclusion, CT-guided 125I brachytherapy is a feasible, effective and safe therapy and may be considered as an alternative option to surgery and radiotherapy for elderly patients with NSCLC.

Keywords: 125I brachytherapy; elderly; non-small cell lung cancer.

Copyright: © Zhao et al.

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85
Oncol Lett
. 2020 Jul;20(1):173-182. doi: 10.3892/ol.2020.11551. Epub 2020 Apr 21.
MALAT1 Knockdown Inhibits Hypopharyngeal Squamous Cell Carcinoma Malignancy by Targeting microRNA-194
Hongming Wang 1, Fei Wang 1, Wenyu Ouyang 1, Xuejun Jiang 1, Wei Li 1
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PMID: 32565945 PMCID: PMC7285813 DOI: 10.3892/ol.2020.11551
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Abstract
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in the oncogenesis and progression of various types of cancer. However, the function of MALAT1 in hypopharyngeal squamous cell carcinoma (HSCC) is not completely understood. In the present study, MALAT1 expression levels were determined using reverse transcription-quantitative PCR, and Cell Counting Kit-8, Transwell and flow cytometry assays were performed to investigate the biological functions of HSCC cells. The results indicated that MALAT1 was upregulated in HSCC. MALAT1 knockdown suppressed HSCC cell proliferation, migration and invasion, and promoted apoptosis compared with the control group. Additionally, microRNA (miR)-194 was identified as a target of MALAT1 and was expressed at low levels in HSCC tissues compared with adjacent non-tumor tissues. A miR-194 agomir inhibited malignant cell behaviors, including cell proliferation, migration and invasion, whereas miR-194 antagomir promoted malignant behaviors compared with the corresponding control groups. In addition, the results suggested that MALAT1 knockdown inhibited the malignant behaviors of HSCC cells by binding miR-194. miR-194 inhibition partially reversed the MALAT1 knockdown-induced inhibitory effects on HSCC cells. Furthermore, MALAT1 knockdown combined with miR194 mimics resulted in the lowest tumor volume among all tested groups in vivo. In conclusion, the results of the present study suggested that MALAT1 knockdown suppressed the malignant behavior of HSCC by targeting miR-194; therefore, MALAT1 may serve as a novel therapeutic target for HSCC.

Keywords: hypopharyngeal squamous cell carcinoma; insulin-like growth factor 1 receptor; metastasis associated lung adenocarcinoma transcript 1; microRNA-194; yes1-associated transcriptional regulator.

Copyright: © Wang et al.

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86
Oncol Lett
. 2020 Jul;20(1):165-172. doi: 10.3892/ol.2020.11538. Epub 2020 Apr 15.
Downregulation of GNA14 in Hepatocellular Carcinoma Indicates an Unfavorable Prognosis
Tao Yu 1, Siyu Lu 2, Wenjing Xie 2
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PMID: 32565944 PMCID: PMC7285778 DOI: 10.3892/ol.2020.11538
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Abstract
Guanine nucleotide-binding protein subunit α14 (GNA14) knockdown was demonstrated to inhibit the proliferation of endometrial carcinoma cells in a recent study; however, its role in hepatocellular carcinoma (HCC) is unknown. In the present study, the clinical significance of GNA14 in HCC was assessed using a dataset of patients with HCC from The Cancer Genome Atlas database. The Integrative Molecular Database of Hepatocellular Carcinoma and Oncomine databases were also used to identify the expression levels of GNA14 in HCC tissues. The association between GNA14 expression levels and clinicopathological features was assessed using the Wilcoxon signed-rank test and logistic regression analysis. Kaplan-Meier curves and Cox regression analysis were applied to evaluate the independent risk factors for clinical outcomes. The present study determined GNA14 DNA methylation levels and tumor-infiltrating immune cells, as well as used Gene Set Enrichment Analysis (GSEA) in HCC. GNA14 mRNA expression levels were lower in HCC compared with normal tissues. Downregulation of GNA14 in HCC was significantly associated with tumor grade, clinical stage and T stage. Furthermore, low expression of GNA14 was an independent predictor for survival outcomes. GNA14 expression levels were partially correlated with the infiltration of B cells and macrophages. Additionally, GSEA analysis revealed that the expression levels of GNA14 were associated with multiple signaling pathways, such as translation, DNA replication, and homologous recombination. In conclusion, low GNA14 expression may be a novel biomarker for diagnosis and prognosis prediction for patients with HCC.

Keywords: GNA14; HCC; TCGA; prognostic marker.

Copyright: © Yu et al.

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87
Oncol Lett
. 2020 Jul;20(1):155-164. doi: 10.3892/ol.2020.11565. Epub 2020 Apr 22.
Hypermethylation of Tumor Necrosis Factor Decoy Receptor Gene in Non-Small Cell Lung Cancer
Yuanlin Qi 1, Lin Qi 1, Minglian Qiu 2, Caiyun Yao 1, Mingfang Zhang 1, Jianbo Lin 2, Zhonghua Zheng 3, Chujia Chen 3, Hongxiang Li 3, Shiwei Duan 3
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PMID: 32565943 PMCID: PMC7286129 DOI: 10.3892/ol.2020.11565
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Abstract
Abnormal methylation of the TNFRSF10C and TNFRSF10D genes has been observed in numerous types of cancer; however, no studies have investigated the methylation of these genes in non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the association between TNFRSF10C and TNFRSF10D methylation and NSCLC. Methylation levels of 44 pairs of NSCLC tumor tissues and distant non-tumor tissues were analyzed using quantitative methylation specific PCR and methylation reference percentage values (PMR). The methylation levels of the TNFRSF10C gene in NSCLC tumor tissue samples were significantly higher compared with those in the distant non-tumor tissues (median PMR, 2.73% vs. 0.75%; P=0.013). Subgroup analysis demonstrated that the methylation levels of TNFRSF10C in tumor tissues from male patients were significantly higher compared with those in distant non-tumor tissues (median PMR, 2.73% vs. 0.75%; P=0.041). The levels of TNFRSF10C methylation were also higher in the tumor tissues of patients who were non-smokers compared with their distant non-tumor tissues (median PMR, 2.50% vs. 0.63%; P=0.013). TNFRSF10C methylation levels were higher in the tumor tissues from male patients compared with those from female patients (median PMR, 2.50% vs. 0.63%; P=0.031). However, no significant differences in the methylation levels of the TNFRSF10D gene were observed between the sexes. Using the cBioPortal and The Cancer Genome Atlas lung cancer data, it was demonstrated that TNFRSF10C methylation levels were inversely correlated with TNFRSF10C mRNA expression levels (r=-0.379; P=0.008). In addition, demethylation of lung cancer cell lines A549 and NCI-H1299 using 5'-aza-deoxycytidine further confirmed that TNFRSF10C hypomethylation was associated with significant upregulation of TNFRSF10C mRNA expression levels [A549 fold-change (FC)=8; P=1.0×10-4; NCI-H1299 FC=3.163; P=1.143×10-5]. A dual luciferase reporter gene assay was also performed with the insert of TNFRSF10C promoter region, and the results revealed that the TNFRSF10C gene fragment significantly enhanced the transcriptional activity of the reporter gene compared with that in the control group (FC=1.570; P=0.032). Overall, the results of the present study demonstrated that hypermethylation of TNFRSF10C was associated with NSCLC.

Keywords: TNFRSF10C; TNFRSF10D; gene methylation; non-small cell lung cancer; promoter.

Copyright: © Qi et al.

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88
Oncol Lett
. 2020 Jul;20(1):145-154. doi: 10.3892/ol.2020.11556. Epub 2020 Apr 21.
Distinct Characteristics of Dasatinib-Induced Pyroptosis in Gasdermin E-expressing Human Lung Cancer A549 Cells and Neuroblastoma SH-SY5Y Cells
Juan Zhang 1, Yang Chen 1, Qiyang He 1
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PMID: 32565942 PMCID: PMC7285962 DOI: 10.3892/ol.2020.11556
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Abstract
Dasatinib, a multikinase inhibitor, is used in the treatment of chronic myeloid leukemia and was developed to overcome imatinib resistance. Its mechanism of action involves the induction of apoptosis, autophagy and necroptosis. However, it remains unclear whether dasatinib can induce pyroptosis. In the present study, gasdermin E (GSDME)-expressing SH-SY5Y and A549 cells were chosen for investigation. Typical pyroptotic features, such as cleavage of GSDME protein, leakage of lactate dehydrogenase and large bubbled morphology, were observed in both cell lines after exposure to dasatinib. The generation of GSDME fragments was inhibited by specific caspase-3 inhibitor zDEVD in SH-SY5Y cells and pan-caspase inhibitor zVAD in A549 cells. Moreover, distinct characteristics of pyroptosis were observed in A549 cells, which occurred only with a high percentage of Annexin V/propidium iodide double-stained cells and low level of GSDME protein cleavage. The sensitivity of A549 cells to dasatinib is significantly reduced by increasing cell numbers. The elevation of GSDMD and GSDME protein levels was induced by low concentrations of dasatinib, which was not influenced by the reduction of p53 protein with RNA interference. In conclusion, to the best of our knowledge, this is the first study to report that dasatinib can induce pyroptosis in tumor cells and increase the protein levels of GSDMD and GSDME in a p53-independent manner.

Keywords: dasatinib; gasdermin D; gasdermin E; p53; pyroptosis; tumor cells.

Copyright: © Zhang et al.

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89
Oncol Lett
. 2020 Jul;20(1):135-144. doi: 10.3892/ol.2020.11540. Epub 2020 Apr 15.
Pathological Roles of c-Met in Bladder Cancer: Association With cyclooxygenase-2, Heme oxygenase-1, Vascular Endothelial Growth factor-A and Programmed Death Ligand 1
Yuta Mukae 1, Yasuyoshi Miyata 1, Yuichiro Nakamura 1, Kyohei Araki 1, Asato Otsubo 1, Tsutomu Yuno 1, Kensuke Mitsunari 1, Tomohiro Matsuo 1, Kojiro Ohba 1, Hideki Sakai 1
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PMID: 32565941 PMCID: PMC7285828 DOI: 10.3892/ol.2020.11540
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Abstract
c-Met is a receptor tyrosine kinase that binds a specific ligand, namely hepatocyte growth factor (HGF). The HGF/c-Met system is important for malignant aggressiveness in various types of cancer, including bladder cancer (BC). However, although phosphorylation is the essential step required for biological activation of c-Met, pathological roles of phosphorylated c-Met at the clinical and molecular levels in patients with BC are not fully understood. In the present study, the expression levels of c-Met and the phosphorylation of two of its tyrosine residues (pY1234/pY1235 and pY1349) were immunohistochemically examined in 185 BC tissues. The associations between these expression levels and cancer cell invasion, metastasis, and cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), VEGF-A and programmed death ligand 1 (PD-L1) levels were investigated. c-Met was associated with muscle invasion (P=0.021), as well as the expression levels of HO-1 (P=0.028) and PD-L1 (P<0.001), whereas pY1349 c-Met was associated with muscle invasion (P=0.003), metastasis (P=0.025), and COX-2 (P=0.017), HO-1 (P=0.031) and PD-L1 (P=0.001) expression. By contrast, pY1234/1235 c-Met was associated with muscle invasion and metastasis (P=0.006 and P=0.012, respectively), but not with the panel of cancer-associated molecules. Furthermore, COX-2 and PD-L1 expression were associated with muscle invasion and metastasis, respectively (P=0.045 and P=0.036, respectively). Hence, c-Met serves important roles in muscle invasion by regulating HO-1 and PD-L1, whereas its phosphorylation at Y1349 is associated with muscle invasion and metastasis via the regulation of COX-2, HO-1 and PD-L1 in patients with BC. Furthermore, phosphorylation at Y1234/1235 may lead to muscle invasion and metastasis via alternate mechanisms associated with c-Met and pY1349 c-Met.

Keywords: bladder cancer; c-Met; cyclooxygenase-2; heme oxygenase-1; phosphorylation; programmed death ligand 1; vascular endothelial growth factor-A.

Copyright: © Mukae et al.

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90
Oncol Lett
. 2020 Jul;20(1):123-134. doi: 10.3892/ol.2020.11539. Epub 2020 Apr 15.
Application of the Chemokine-Chemokine Receptor Axis Increases the Tumor-Targeted Migration Ability of Cytokine-Induced Killer Cells in Patients With Colorectal Cancer
Yunlian Zou 1 2, Jianhua Liang 1 2, Danyang Li 1 2, Jingjing Fang 1 2, Linping Wang 2, Jinli Wang 2, Jinping Zhang 2, Qiang Guo 3, Xinmin Yan 1 2, Hui Tang 1 2
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PMID: 32565940 PMCID: PMC7286113 DOI: 10.3892/ol.2020.11539
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Abstract
Cytokine-induced killer (CIK) cells are a group of heterogeneous immune cells which can be isolated from human peripheral blood mononuclear cells and have demonstrated therapeutic benefit both in hematologic malignancies and solid tumors, including colorectal cancer. However, poor tumor-targeted migration has limited the clinical efficacy of CIK cell treatment. The chemokine-chemokine receptor (CK-CKR) axis serves a role in the tumor-directed trafficking capacity of immune cells. Investigating the relationship between CKR profiles on the surface of CIK cells and chemokine expression levels in the tumor microenvironment may improve CIK cell therapy. In the present study, the spectrum of chemokine expression levels in tumor tissues from patients with colorectal cancer (CRC) and CKR expression profiles in CIK cells obtained from the same individuals with CRC were investigated. The results showed that chemokine expression levels in tumor tissues exhibited variability and cell line heterogeneity. However, the expression levels of a number of chemokines were similar in different CRC donors and cell lines. Expression levels of CXCLL10, CXCL11 and CCL3 were significantly higher in most tumor tissues compared with adjacent normal tissues and highly expressed in most CRC cell lines. In accordance with chemokine expression levels, CKR profiles on the surface of CIK cells also showed donor-to-donor variability. However, concordant expression profiles of CKRs were identified in different patients with CRC. CXCR3 and CXCR4 were highly expressed on the surface of CIK cells through the culture process. Importantly, the expression levels of all CKRs, especially CCR4, CXCR4 and CXCR3, were notably decreased during the course of CIK cell expansion. The changing trend of CKR profiles were not correlated with the chemokine expression profiles in CRC tissues (CCL3, CXCL12 and CXCL10/CXCL11 were highly expressed in CRC tissue). Re-stimulating CIK cells using chemokines (CCL21 and CXCL11) at the proper time point increased corresponding CKR expression levels on the surface of CIK cells and enhance tumor-targeted trafficking in vitro. These results demonstrated that modification of the CK-CKR axis using exogenous recombinant chemokines at the proper time point enhanced CIK cell trafficking ability and improved CIK antitumor effects.

Keywords: chemokine; chemokine receptors; colorectal cancer; cytokine induce killer cells; immunotherapy.

Copyright: © Zou et al.

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91
Oncol Lett
. 2020 Jul;20(1):113-122. doi: 10.3892/ol.2020.11558. Epub 2020 Apr 21.
Bioinformatics Analysis of Prognosis-Related Long Non-Coding RNAs in Invasive Breast Carcinoma
Yuanyuan Hu 1, Xidong Gu 1, Yin Duan 1, Yong Shen 1, Xiaohong Xie 1
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PMID: 32565939 PMCID: PMC7285808 DOI: 10.3892/ol.2020.11558
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Abstract
Breast cancer is one of the most common types of cancer among women worldwide and needs more sensitive prognostic biomarkers to improve its treatment. In the present study, differentially expressed long non-coding RNAs (lncRNAs) in invasive breast carcinoma from The Cancer Genome Atlas and cBioPortal database were investigated, identifying 292 differentially expressed lncRNAs in 1,100 cases. By analyzing the overall survival rate, 10 lncRNAs were significantly correlated with poor prognosis. To explore the underlying molecular mechanisms of the 10 prognosis-related lncRNAs, bioinformatic methods were used to predict the potential target miRNAs, mRNAs and proteins, and to construct a lncRNA-miRNA-mRNA regulatory network and lncRNA-protein interaction network. Finally, the functions of the target genes and proteins were insvestigated using Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses. The results showed that these 10 lncRNAs could be novel prognostic markers for invasive breast carcinoma and the present study aimed to provide novel insight into the diagnosis and treatment of breast cancer.

Keywords: competitive endogenous RNA network; invasive breast carcinoma; long non-coding RNA-protein interaction; overall survival; prognosis.

Copyright: © Hu et al.

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92
Oncol Lett
. 2020 Jul;20(1):99-112. doi: 10.3892/ol.2020.11544. Epub 2020 Apr 15.
Metastasis-associated Gene MAPK15 Promotes the Migration and Invasion of Osteosarcoma Cells via the c-Jun/MMPs Pathway
Zexin Su 1, Bingsheng Yang 2, Zhirui Zeng 3, Shuang Zhu 2, Chenyang Wang 4, Shan Lei 3, Yongfa Jiang 1, Lijun Lin 2
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PMID: 32565938 PMCID: PMC7285714 DOI: 10.3892/ol.2020.11544
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Abstract
Osteosarcoma (OS) is the most common and destructive primary bone malignancy to affect children and adolescents. Metastases remain the primary cause of death in patients with OS. In the present study, weight gene co-expressed network analysis (WGCNA) and differentially-expressed gene analysis were used to identify key genes associated with the metastasis of OS. Reverse transcription-quantitative PCR and immunohistochemical staining were then used to detect the expression levels of these key genes in OS tissues, and to determine the hub genes of interest. Wound-healing and transwell assays, in addition to a lung metastasis model, were used to detect the effects of the hub genes on OS cell proliferation and metastasis in vitro and in vivo. Using WGCNA and differential expression analysis, deleted in lung and esophageal cancer protein 1 (DLEC1), Forkhead box J1 (FOXJ1) and mitogen-activated protein kinase 15 (MAPK15) were predicted to be key metastasis-associated genes, and highly expressed in metastatic OS tissues; among them, the protein and mRNA expression levels of MAPK15 were most significantly increased in our OS tissues from patients who exhibited metastases at diagnosis, and thus MAPK15 was determined to be a metastasis-associated hub gene to further study. Furthermore, inhibiting MAPK15 expression significantly decreased OS cell metastasis in vitro and in vivo, as well as suppressing c-Jun/matrix metalloproteinase (MMP)-associated pathways. Overexpression of MAPK15 activated the c-Jun/MMPs pathway and promoted OS cell metastasis, while inhibition of c-Jun blocked this effect. Taken together, MAPK15 was indicated to be an OS metastasis-associated gene, and was confirmed to promote the migration and invasion of OS cells via the c-Jun/MMP pathway. MAPK15 may therefore be an effective target for the treatment of OS.

Keywords: differently expressed analysis; metastasis; mitogen-activated protein kinase 15; osteosarcoma; weighted gene co-expression network analysis.

Copyright: © Su et al.

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93
Oncol Lett
. 2020 Jul;20(1):85-98. doi: 10.3892/ol.2020.11575. Epub 2020 Apr 27.
Prognostic Prediction of a 12-methylation Gene-Based Risk Score System on Pancreatic Adenocarcinoma
Daoqin Dou 1, Shaohua Yang 1, Jiren Zhang 2
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PMID: 32565937 PMCID: PMC7285752 DOI: 10.3892/ol.2020.11575
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Abstract
Pancreatic adenocarcinoma (PAAD) accounts for ~85% of all pancreatic cancer cases and is associated with a less favorable prognosis. Aberrant DNA methylation may influence the progression of PAAD by inducing abnormal gene expression. Methylation data of PAAD samples with prognosis information were obtained from The Cancer Genome Atlas (training set) and European Bioinformatics Institute Array Express databases (validation sets). Using the limma package, the differentially methylated genes in the training dataset were screened. Combined with the Weighted Gene Co-expression Network Analysis package, the co-methylated genes in key modules were identified. Then, a cor.test function in R software was applied to explore the functions of key the methylated genes. Correlation analyses of the expression levels and methylation levels of key methylated genes were performed, followed by identification of methylated genes associated with prognosis using Univariate Cox regression analysis. The optimal combination of prognosis related methylated genes was determined using a Cox-Proportional Hazards (Cox-PH) model. Subsequently, the risk score prognostic prediction system was constructed by combining the Cox-PH prognosis coefficients of the selected optimized genes. Based on the constructed risk score system, samples in all datasets were divided into high and low risk samples and the survival status was compared using survival curves. Furthermore, the correlation between independent prognostic factors and the risk score system was determined using the survival package. A total of 50 genes associated with prognosis of PAAD and a 12-gene optimal combination were obtained, including: CCAAT/enhancer binding protein α, histone cluster 1 H4E, STAM binding protein-like 1, phospholipase D3, centrosomal protein 55, ssDNA binding protein 4, glutamate AMPA receptor subunit 1, switch-associated protein 70, adenylate-cyclase activating polypeptide 1 receptor 1, yippee-like 3, homeobox C4 and insulin-like growth factor binding protein 1. Subsequently, a risk score prognostic prediction system of these 12 genes was constructed and validated. In addition, pathological N category, radiotherapy and risk status were identified as independent prognostic factors. Overall, the risk score prognostic prediction system constructed in the present study may be effective for predicting the prognosis of patients with PAAD.

Keywords: correlation analysis; differentially methylated genes; pancreatic adenocarcinoma; risk score system; weighted gene co-expression network analysis.

Copyright: © Dou et al.

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94
Oncol Lett
. 2020 Jul;20(1):75-84. doi: 10.3892/ol.2020.11542. Epub 2020 Apr 15.
Integrative Transcriptome Analysis Identified a BMP Signaling Pathway-Regulated lncRNA AC068643.1 in IDH Mutant and Wild-Type Glioblastomas
Guo-Hao Huang 1, Yu-Chun Pei 1, Lin Yang 1, Ke-Jie Mou 2, Jun-Hai Tang 1, Yan Xiang 1, Jun Liu 1, Sheng-Qing Lv 1
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PMID: 32565936 PMCID: PMC7285920 DOI: 10.3892/ol.2020.11542
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Abstract
Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (IDH) mutant (IDH MT) and wild-type (IDH WT) subtypes, and each is associated with distinct tumor behavior and prognosis. The present study aimed to investigate differentially expressed long non-coding (lnc)RNAs and mRNAs between IDH MT and IDH WT GBMs, as well as to explore the interaction and potential functions of these RNAs. A total of 132 GBM samples with RNA profiling data (10 IDH MT and 122 IDH WT cases) were obtained from The Cancer Genome Atlas, and 62/78 and 142/219 up/downregulated lncRNAs and mRNAs between IDH MT and IDH WT GBMs were identified, respectively. Multivariate Cox analysis of the dysregulated lncRNAs/mRNAs identified three-lncRNA and fifteen-mRNA signatures with independent prognostic value, indicating that these RNAs may serve roles in determining distinct tumor behaviors and prognosis of patients with IDH MT/WT GBMs. Functional analysis of the three lncRNAs revealed that they were primarily associated with cell stemness or differentiation. Pearson's correlation analysis revealed that the protective lncRNA AC068643.1 was significantly positively correlated with two key bone morphogenetic protein (BMP) signaling-associated mRNAs, Bone morphogenetic protein 2 (BMP2) and Myostatin (MSTN), from the 15 mRNAs. Further in vitro studies demonstrated that BMP2 and MSTN directly stimulated AC068643.1 expression. In conclusion, the present study identified a BMP signaling pathway-regulated lncRNA AC068643.1, which may contribute to the different tumor behaviors observed between IDH MT and IDH WT GBMs.

Keywords: IDH mutation; glioblastoma; lncRNA; prognostic; stemness.

Copyright: © Huang et al.

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95
Oncol Lett
. 2020 Jul;20(1):67-74. doi: 10.3892/ol.2020.11568. Epub 2020 Apr 23.
Ubiquitin-specific Peptidase 17 Promotes Cisplatin Resistance via PI3K/AKT Activation in Non-Small Cell Lung Cancer
Shengchao Zhang 1, Zhenglang Xu 1, Jun Yuan 1, Hao Chen 1
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PMID: 32565935 PMCID: PMC7286115 DOI: 10.3892/ol.2020.11568
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Abstract
The suppression of ubiquitin-specific peptidase 17 (USP17) has previously been found to result in reduced tumorigenesis and invasion of non-small cell lung cancer (NSCLC) cells. However, the functions and underlying mechanisms of USP17 in NSCLC progression remain unclear. In the present study, cisplatin treatment was found to upregulate USP17 expression in a dose-dependent manner. Furthermore, USP17-overexpressing (USP17-OE) NSCLC A549 and H1299 cells were generated for mechanistic studies. The results from the Cell Counting Kit-8 assay revealed increased cell proliferation in USP17-OE cells compared with that of control cells. Moreover, the viability of USP17-OE cells was significantly higher than that of the control cells, when treated with cisplatin. The results of the biochemical studies demonstrated enhanced PI3K and AKT phosphorylation in USP17-OE NSCLC cells, whereas USP17-knockdown decreased these levels of phosphorylation. By contrast, an AKT inhibitor abolished the USP17-mediated enhancement of proliferation. Moreover, suppression of USP17 or the combination of the AKT inhibitor and cisplatin significantly reduced cell viability. Overall, the results of the present study suggest that PI3K/AKT activation is the underlying mechanism of USP17-mediated cisplatin resistance in NSCLC.

Keywords: AKT inhibitor; cisplatin; non-small cell lung cancer; ubiquitin-specific peptidase 17.

Copyright: © Zhang et al.

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96
Oncol Lett
. 2020 Jul;20(1):61-66. doi: 10.3892/ol.2020.11554. Epub 2020 Apr 21.
AMPK Decreases ERK1/2 Activity and Cancer Cell Sensitivity to Nutrition Deprivation by Mediating a Positive Feedback Loop Involving eEF2K
Shujuan Tong 1, Tao Zhou 1 2, Yufen Meng 1, Dongqin Xu 1, Jianping Chen 1
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PMID: 32565934 PMCID: PMC7286132 DOI: 10.3892/ol.2020.11554
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Abstract
Nutrition deprivation (ND) is a common feature of the tumor microenvironment. Tumor cells, therefore, frequently develop resistance mechanisms against ND. One of these mechanisms is the activation of the AMP-activated protein kinase (AMPK), which promotes cell survival under ND. AMPK activation promotes the activity of eukaryotic elongation factor 2 kinase (eEF2K), thereby blocking protein synthesis. The results of the present study indicated the inhibiting effect of AMPK activation on mitogen-activated protein kinase (ERK1/2) activity, which in turn downregulates G1/S transition and promotes cell survival by mediating eEF2K under ND. The knockdown of ERK1/2 enhances cancer cell survival under ND. In the presence of nutrients, eEF2k interacts with dual-specificity mitogen-activated protein kinase kinase (MEK)1/2, conferring a positive feedback loop via MEK1/2-ERK1/2-ribosomal protein S6 kinase α-1-eEF2K signaling, leading to the constitutive activation of ERK1/2. By contrast, under acute ND, AMPK activation blocked the interaction between eEF2K and MEK1/2, contributing to the increased resistance of cancer cells to ND. The present findings reveal a previously undiscovered mechanism that uses AMPK activation to mediate ERK1/2-regulated protein synthesis and cell survival by inhibiting eEF2K-MEK1/2 interaction under ND conditions.

Keywords: AMP-activated protein kinase; eukaryotic elongation factor 2 kinase; nutrition deprivation; positive feedback loop.

Copyright: © Tong et al.

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97
Oncol Lett
. 2020 Jul;20(1):53-60. doi: 10.3892/ol.2020.11567. Epub 2020 Apr 22.
Chloroquine Increases the Anti-Cancer Activity of Epirubicin in A549 Lung Cancer Cells
Ai-Ling Liang 1 2, Jing Zhang 3, Shen-Lin Du 4, Bin Zhang 2 5, Xuan Ma 2 5, Cui-Yun Wu 3, Yong-Jun Liu 2 5
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PMID: 32565933 PMCID: PMC7285842 DOI: 10.3892/ol.2020.11567
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Abstract
The present study investigated whether the autophagy inhibitor chloroquine (CQ) can improve the sensitivity of the A549 lung cancer cell line to epirubicin (EPI). The Cell Counting Kit 8 (CCK8) assay was used to determine the EPI IC50 in A549 cells treated for 72 h. A549 cells were treated with Western blot analysis was performed to detect the expression level of the autophagy-associated protein, microtubule associated protein 1 light chain 3 β (LC3B), and apoptosis-associated proteins such as cleaved caspase-9 and cleaved caspase-3. CCK8, colony formation, wound healing and Transwell assays were performed to analyze cell proliferation, migration and invasion capacity. Reverse transcription-quantitative PCR (RT-qPCR) was used to analyze the mRNA expression levels of LC3B and beclin-1, and the apoptosis rate was analyzed by flow cytometry. The IC50 of EPI was 0.03 µg/ml. The CCK8 results demonstrated that the cell survival rate was lower in CQ + EPI-treated cells when compared with the individual treatment groups. The colony formation results revealed that the number of clones in the EPI + CQ-treated group was reduced compared with EPI or CQ treatment alone. The wound healing assay revealed that migration was reduced in the EPI + CQ-treated group compared with the other treatment groups, and the Transwell results indicated that the number of cells passing through the Matrigel and membrane was lowest in the CQ + EPI treatment group. The mRNA expression levels of LC3B and beclin-1 were increased in the CQ + EPI group by 51.5 and 61.2%, respectively, when compared with the control group. The results indicated that LC3B protein expression was enhanced by EPI in a concentration-dependent manner, and the protein levels of cleaved caspase-3 and cleaved caspase-9 were higher in the combination group than in the EPI alone group. The flow cytometry results demonstrated that the apoptosis rate was highest in the EPI + CQ group. In conclusion, the autophagy inhibitor CQ increased the sensitivity of A549 cells to EPI, and the underlying mechanism of action may be associated with the activation of apoptosis.

Keywords: autophagy; chemotherapy resistance; chloroquine; epirubicin; lung cancer.

Copyright: © Liang et al.

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98
Oncol Lett
. 2020 Jul;20(1):43-52. doi: 10.3892/ol.2020.11560. Epub 2020 Apr 21.
YRDC Is Upregulated in Non-Small Cell Lung Cancer and Promotes Cell Proliferation by Decreasing Cell Apoptosis
Haibo Shen 1, Enkuo Zheng 1, Zhenhua Yang 1, Minglei Yang 1, Xiang Xu 1, Yinjie Zhou 1, Junjun Ni 1, Rui Li 1, Guofang Zhao 1
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PMID: 32565932 PMCID: PMC7285791 DOI: 10.3892/ol.2020.11560
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Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality worldwide. yrdC N6-threonylcarbamoltransferase domain containing protein (YRDC) has been demonstrated to be involved in the formation of threonylcarbamoyladenosine in transfer ribonucleic acid. However, the molecular mechanisms underlying NSCLC progression remain largely unclear. The present study revealed that YRDC was upregulated in NSCLC samples compared with adjacent non-cancerous tissues by analyzing datasets obtained from the Gene Expression Omnibus and The Cancer Genome Atlas. Higher expression of YRDC was associated with overall survival time and disease-free survival time in patients with NSCLC, particularly in lung adenocarcinoma. Furthermore, knockdown of YRDC in NSCLS cell lines significantly suppressed cell growth and cell colony formation in vitro. Additionally, the results demonstrated that silencing of YRDC induced apoptosis of A549 cells. Then, the protein-protein interaction networks associated with yrdC N6-threonylcarbamoltransferase domain containing protein (YRDC) in NSCLC were subsequently constructed to investigate the potential molecular mechanism underlying the role of YRDC in NSCLC. The results revealed that YRDC was involved in the regulation of spliceosomes, ribosomes, the p53 signaling pathway, proteasomes, the cell cycle and DNA replication. The present study demonstrated that YRDC may serve as a novel biomarker for the prognosis prediction and treatment of NSCLC.

Keywords: apoptosis; biomarker; non-small cell lung cancer; proliferation; yrdC N6-threonylcarba-moltransferase domain containing protein.

Copyright: © Shen et al.

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99
Oncol Lett
. 2020 Jul;20(1):33-42. doi: 10.3892/ol.2020.11553. Epub 2020 Apr 21.
Visceral Obesity and Cell Cycle Pathways Serve as Links in the Association Between Bisphenol A Exposure and Breast Cancer
Tsu-Nai Wang 1 2, Pei-Jing Yang 1, Yu-Ting Tseng 1, Yi-Shan Tsai 1, Po-Lin Kuo 2 3, Chien-Chih Chiu 2 4, Shih-Shin Liang 4 5, Tsung-Hua Hsieh 6, Ming-Feng Hou 3 7 8 9 10, Eing-Mei Tsai 2 6 11 12
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PMID: 32565931 PMCID: PMC7285711 DOI: 10.3892/ol.2020.11553
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Abstract
It has been identified that bisphenol A (BPA) exposure causes developmental toxicity in breast cells. However, the exact molecular mechanisms underlying the association between exposure to BPA and breast cancer remain unclear. The aim of the present study was to investigate the BPA-regulated signaling pathways associated with the aggressiveness and the development of breast cancer. Microarray technology and functional gene set analyses were used to evaluate BPA and breast cancer-associated biomarkers and pathways in a discovery-driven manner. Using individual dataset analyses, it was indicated that two BPA-associated gene sets, the visceral obesity pathway, involved in visceral fat deposits and the metabolic syndrome, and the cell cycle pathway, involved in cyclins and cell cycle regulation, were significantly associated with a high grade of aggressiveness and the development of estrogen receptor (ER)-positive breast cancer (between P<0.05 and 0.0001). The pooled analysis indicated that the most significant pathway was G1/S checkpoint regulation, and the cyclin and cell cycle regulation pathway for BPA-associated ER-positive cancer. Cancer cell signaling pathways were associated with healthy breast cells developing into breast cancer. The visceral obesity and the cell cycle pathways were indicated to link BPA exposure to breast cancer. The results of the present study demonstrate a significant association between breast cancer and BPA-regulated gene pathways.

Keywords: bisphenol A; breast cancer; gene sets; microarray; pathway.

Copyright: © Wang et al.

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100
Review Oncol Lett
. 2020 Jul;20(1):19-32. doi: 10.3892/ol.2020.11566. Epub 2020 Apr 22.
Endocrine Disruptors From the Environment Affecting Breast Cancer
Gloria M Calaf 1 2, Richard Ponce-Cusi 1, Francisco Aguayo 3 4, Juan P Muñoz 1, Tammy C Bleak 1
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PMID: 32565930 PMCID: PMC7286136 DOI: 10.3892/ol.2020.11566
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Abstract
Evaluation of carcinogenic substances from the environment is a challenge for scientists. Recently, a novel approach based on 10 key characteristics of human carcinogens classified by the International Agency for Research on Cancer (IARC) has emerged. Carcinogenesis depends on different mechanisms and factors, including genetic, infectious (bacteria, viruses) and environmental (chemicals) factors. Endocrine disruptors are exogenous chemicals that can interfere and impair the function of the endocrine system due to their interaction with estrogen receptors or their estrogen signaling pathways inducing adverse effects in the normal mammary development, originating cancer. They are heterogeneous chemicals and include numerous synthetic substances used worldwide in agriculture, industry and consumer products. The most common are plasticizers, such as bisphenol A (BPA), pesticides, such as dichlorodiphenyltrichloroethane, and polychlorinated biphenyls (PCBs). Xenoestrogens appear to serve an important role in the increased incidence of breast cancer in the United States and numerous other countries. Several studies have demonstrated the role of organochlorine xenoestrogens in breast cancer. Therefore, the overall cumulative exposure of women to estrogens results in an increased risk for this type of cancer. Factors like lifestyle and diet also serve a role in the increased incidence of this disease. The aim of the present study was to analyze these chemical compounds based on the key characteristics given by the IARC, with a special focus on breast cancer, to establish whether these compounds are carcinogens, and to create a model for future analysis of other endocrine disruptors.

Keywords: bisphenol A; cancer; dichlorodiphenyltrichloroethane; endocrine disruptors; polychlorinated biphenyls.

Copyright: © Calaf et al.

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