Search

Background: Platinum based therapy is commonly used in the treatment of advanced gastric cancer. However, resistance to chemotherapy is a major challenge that causes marked variation in individual response rate and survival rate. In this study, we aimed to identify the expression of GTSE1 and its correlation with cisplatin resistance in gastric cancer cells. Methods: Methylation profiling was carried out in tissue samples from gastric cancer patients before undergoing neoadjuvent therapy using docetaxel, cisplatin and 5FU (DCX) and in gastric cancer cell lines. The correlation between GTSE1 expression and methylation in gastric cancer cells was determined by RT-PCR and MSP respectively. GTSE1 expression was knocked-down using shRNA's and its effects on cisplatin cytotoxicity and cell survival were detected by MTS, proliferation and clonogenic survival assays. Additionally, the effect of GTSE1 knock down in drug induced apoptosis was determined by western blotting and apoptosis assays. Results: GTSE1 exhibited a differential methylation index in gastric cancer patients and in cell lines that correlated with DCX treatment response and cisplatin sensitivity, respectively. In-vitro, GTSE1 expression showed a direct correlation with hypomethylation. Interestingly, Cisplatin treatment induced a dose dependent up regulation as well as nuclear translocation of GTSE1 expression in gastric cancer cells. Knock down of GTSE1 enhanced cisplatin cytotoxity and led to a significant reduction in cell proliferation and clonogenic survival. Also, loss of GTSE1 expression caused a significant increase in P53 mediated apoptosis in cisplatin treated cells. Conclusion: Our study identifies GTSE1 as a biomarker for cisplatin resistance in gastric cancer cells. This study also suggests the repressive role of GTSE1 in cisplatin induced apoptosis and signifies its potential utility as a therapeutic target for better clinical management of gastric cancer patients. [ABSTRACT FROM AUTHOR]

Background: Platinum based therapy is commonly used in the treatment of advanced gastric cancer. However, resistance to chemotherapy is a major challenge that causes marked variation in individual response rate and survival rate. In this study, we aimed to identify the expression of GTSE1 and its correlation with cisplatin resistance in gastric cancer cells. Methods: Methylation profiling was carried out in tissue samples from gastric cancer patients before undergoing neoadjuvent therapy using docetaxel, cisplatin and 5FU (DCX) and in gastric cancer cell lines. The correlation between GTSE1 expression and methylation in gastric cancer cells was determined by RT-PCR and MSP respectively. GTSE1 expression was knocked-down using shRNA’s and its effects on cisplatin cytotoxicity and cell survival were detected by MTS, proliferation and clonogenic survival assays. Additionally, the effect of GTSE1 knock down in drug induced apoptosis was determined by western blotting and apoptosis assays. Results: GTSE1 exhibited a differential methylation index in gastric cancer patients and in cell lines that correlated with DCX treatment response and cisplatin sensitivity, respectively. In-vitro, GTSE1 expression showed a direct correlation with hypomethylation. Interestingly, Cisplatin treatment induced a dose dependent up regulation as well as nuclear translocation of GTSE1 expression in gastric cancer cells. Knock down of GTSE1 enhanced cisplatin cytotoxity and led to a significant reduction in cell proliferation and clonogenic survival. Also, loss of GTSE1 expression caused a significant increase in P53 mediated apoptosis in cisplatin treated cells. Conclusion: Our study identifies GTSE1 as a biomarker for cisplatin resistance in gastric cancer cells. This study also suggests the repressive role of GTSE1 in cisplatin induced apoptosis and signifies its potential utility as a therapeutic target for better clinical management of gastric cancer patients. [ABSTRACT FROM AUTHOR]

Background: Most previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites. In the present study we performed comprehensive DNA methylation profiling of CRC with the aim of characterizing CIMP subgroups. Methods: DNA methylation at 1,505 CpG sites in 807 cancer-related genes was evaluated using the Illumina GoldenGate® methylation array in 28 normal colonic mucosa and 91 consecutive CRC samples. Methylation data was analyzed using unsupervised hierarchical clustering. CIMP subgroups were compared for various clinicopathological and molecular features including patient age, tumor site, microsatellite instability (MSI), methylation at a consensus panel of CpG islands and mutations in BRAF and KRAS. Results: A total of 202 CpG sites were differentially methylated between tumor and normal tissue. Unsupervised hierarchical clustering of methylation data from these sites revealed the existence of three CRC subgroups referred to as CIMP-low (CIMP-L, 21% of cases), CIMP-mid (CIMP-M, 14%) and CIMP-high (CIMP-H, 65%). In comparison to CIMP-L tumors, CIMP-H tumors were more often located in the proximal colon and showed more frequent mutation of KRAS and BRAF (P < 0.001). Conclusions: Comprehensive DNA methylation profiling identified three CRC subgroups with distinctive clinicopathological and molecular features. This study suggests that both KRAS and BRAF mutations are involved with the CIMP-H pathway of CRC rather than with distinct CIMP subgroups. [ABSTRACT FROM AUTHOR]

Background: Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase responsible for regulating ribosomal biogenesis and protein synthesis. Dysregulation of mTOR contributes to tumorigenesis, angiogenesis, cellular growth and metastasis but its roles in esophageal squamous cell carcinoma (ESCC) are controversial. Therefore, the objective of this study is to evaluate the prognostic and clinicopathological significance of mTOR/p-mTOR expression in ESCC., Methods: Literature retrieval was conducted by searching PubMed, EMBASE and the Web of Science for full-text papers that met our eligibility criteria. Odds ratio (OR) and hazard ratio (HR) with 95 % confidence interval (CI) served as the appropriate summarized statistics for assessments of clinicopathological and prognostic significance, respectively. Cochrane Q-test and I 2 -statistic were adopted to estimate the heterogeneity level between studies. Potential publication bias was detected by Begg's test and Egger's test., Results: A total of 915 ESCC patients from nine original articles were included into this meta-analysis. The pooled analyses suggested that mTOR/p-mTOR expression was significantly correlated with the unfavorable outcomes of differentiation degree (OR: 2.63; 95 % CI: 1.71-4.05; P = 0.001), tumor invasion (OR: 1.48; 95 % CI: 1.02-2.13; P = 0.037), TNM stage (OR: 2.25; 95 % CI: 1.05-4.82; P = 0.037) and lymph node metastasis (OR: 1.82; 95 % CI: 1.06-3.11; P = 0.029), but had no significant relationship to the genders (OR: 0.81; 95 % CI: 0.50-1.32; P = 0.396). Moreover, mTOR/p-mTOR expression could independently predict the worse overall survival (HR: 2.04; 95 % CI: 1.58-2.62; P < 0.001), disease-free survival (HR: 2.39; 95 % CI: 1.64-3.49; P < 0.001) and cancer-specific survival (HR: 1.62; 95 % CI: 1.18-2.23; P = 0.003) of patients with ESCC. Such prognostic value of mTOR was not substantially altered by further subgroup analyses., Conclusions: Positive expression of mTOR and p-mTOR was significantly associated with the unfavorable conditions on the depth of tumor invasion, TNM stage, differentiation degree and lymph node metastasis. mTOR and p-mTOR could serve as a valuable predictor for the poor prognosis of ESCC. More high-quality worldwide studies performing a multivariate analysis based on larger sample size are urgently required for further verifying and modifying our findings in the future.