Overall Survival In Gastric Cancer Research Articles

Correlation of CHAF1A with adjuvant chemotherapy outcome and microsatellite instability in gastric cancer.

e15511 Background: Clinical outcomes of adjuvant chemotherapy in gastric cancer (GC) have considerable stage-independent variability, which underscores the need for predictive molecular markers. Previous studies indicated that CHAF1A played a critical role in tumor growth, but whether it was associated with adjuvant chemotherapy in GC was still unknown. This retrospective study investigated the prognostic value of CHAF1A in adjuvant chemotherapy of GC. Methods: A total of 325 stage IB-III patients with fluoropyrimidines (FU)-based adjuvant chemotherapy after curative D2 gastrectomy meeting eligibility criteria were selected. CHAF1A protein expression was determined by immunohistochemical method. The primary outcomes were Overall survival (OS) and Disease-free survival (DFS). Kaplan-Meier method was used to estimate survival curve and Cox model for multifactor analysis. Results: CHAF1A mRNA was overexpressed in GC tissues and positive CHAF1A protein expression was not associated with OS and DFS in overall patients treated by FU-based chemotherapy ( P = 0.391 and 0.511, respectively). However, as stratified by tumor sites, positive CHAF1A expression was associated with poor OS and DFS in non-cardia cancer ( P = 0.009 and 0.007, respectively) but not in cardia cancer ( P = 0.229 and 0.112, respectively). Multivariate analysis indicated that CHAF1A expression level was still an independent predictor for both OS (HR = 2.42; 95% CI: 1.12-5.20; P = 0.024) and DFS (HR = 1.91; 95% CI: 1.03-3.54; P = 0.039) in non-cardia GC. Furthermore, CHAF1A was correlated with the status of microsatellite instability ( P = 0.025). Conclusions: CHAF1A might be a predictor for outcomes of FU-based adjuvant chemotherapy in patients with non-cardia GC, but needed further prospective studies to confirm.

The ubiquitin ligase CHIP modulates cellular behaviors of gastric cancer cells by regulating TRAF2

BackgroundCHIP is an E3 ubiquitin ligase that plays contrast roles in diverse human malignancies, depending on its targets. To date, the mechanisms underlying the function of CHIP in gastric cancer remains unclear. Here, we aim to further clarify the effects of CHIP on the development and progression of gastric cancer and explore its potential target.MethodsStably transfected CHIP-shRNA and TRAF2-shRNA AGS gastric cancer cell lines were established using Lipofectamine 2000. Cell growth was measured by an xCelligence real-time monitoring system and colony formation assay. Cell proliferation was detected using CCK-8, Ki-67, or CFSE assays. Apoptosis was detected by TUNEL assay or Annexin V/PI-staining followed by flow cytometric analysis. Cell cycle distribution was detected by PI-staining followed by flow cytometric analysis. Cell migration and invasion abilities were measured by a real-time xCelligence system, Transwell insert, and scratch assays. The expression of cell cycle-related proteins, apoptosis-related proteins, AKT, ERK, NF-κB signaling subunits, MMP2, MMP9, and Integrin β-1 were detected by Western blotting analysis. NF-κB DNA-binding capability was quantified using an ELISA-based NF-κB activity assay. Gastric cancer tissue microarray was analyzed to investigate the expression of both CHIP and TRAF2, and their clinical significance.ResultsThe CHIP-silencing in the AGS cells was oncogenic evidenced by the appearance of capable of anchorage-independent growth. The CHIP-silencing significantly enhanced the AGS cell proliferation capability likely due to the induced phosphorylation of ERK. The CHIP-silencing significantly inhibited apoptosis due to increased expression of Bcl-2. The CHIP-silencing promoted the AGS cell migration and invasion abilities, likely by regulating the expression of Integrin β-1. TRAF2 expression was markedly decreased in the CHIP-overexpressing cells at protein level, but not at mRNA level. The TRAF2-silencing markedly inhibited the proliferation ability of the AGS cells, the defected cell proliferation and enhanced apoptosis were involved in. The TRAF2-silencing also attenuated the cell migration and invasion capacities of the AGS cells. Furthermore, the expression of CHIP was downregulated while the expression of TRAF2 was upregulated in gastric cancer tissues. TRAF2 expression is independent prognostic factors of gastric cancer. The expression of CHIP and TRAF2 was negatively correlated in the gastric cancer tissue. Lower CHIP or higher TRAF2 was significantly linked to shorter overall survival in gastric cancer patients.ConclusionsTRAF2 influenced diverse aspects of cellular behavior of gastric cancer cells, including cell growth, migration, and invasion, which was in contrast to the functions of CHIP. TRAF2 could be considered as an independent prognostic factor in gastric cancer patients. It is possible that TRAF2 was a substrate of CHIP and CHIP regulated the TRAF2/NF-κB axis, which modulated diverse cellular behaviors in the AGS gastric cancer cells.

Clinical Impact of Sarcopenia on Gastric Cancer.

Sarcopenia is a complex syndrome defined by progressive and generalized loss of skeletal muscle mass and strength. Although sarcopenia is mainly associated with aging, cancer is also one of its causes. Sarcopenia is now drawing attention as a poor prognostic factor in cancer. In patients with gastric cancer associated with eating disorders that often leads to loss of weight and muscle, sarcopenia is particularly important. Its definition and method of assessment, however, vary between studies, thus these need to be standardized. Nevertheless, emerging evidence suggests that sarcopenia contributes independently to postoperative complications and overall survival in gastric cancer. Interventions preventing sarcopenia with targeted nutrition and exercise are currently explored. This review aims to provide an understanding of sarcopenia, emphasizing its importance in the management of gastric cancer.

Implication of lymph node staging in migration and different treatment strategies for stage T2N0M0 and T1N1M0 resected gastric cancer: a SEER population analysis

PurposeThe purpose of this study was to explore the differences between stage T2N0M0 and stage T1N1M0 gastric cancer (GC) and to identify the necessity of adjuvant treatment (AT) for these stages.MethodsBetween years 2004 and 2015, 1971 stage IB GC patients who underwent radical surgery were recruited using the Surveillance, Epidemiology and End Results database. We conducted univariate/multivariate analyses, the propensity score matching and evaluated gastric cancer-specific survival (GCSS) and overall survival (OS) with the log-rank test.ResultsT1N1M0 had a significantly worse survival than T2N0M0 in both GCSS and OS before and after the propensity score matching. Examined lymph nodes (ELN) ≤ 15 and T1N1M0 were independent risk factors for worse GCSS and OS in stage IB GC. The absence of adjuvant chemotherapy (CT) was an independent risk factor for worse GCSS and OS in T1N1M0 but not in T2N0M0. AT demonstrated similar GCSS and OS with surgery alone (SA) for T2N0M0 but better survival for T1N1M0. Compared to CT and adjuvant chemoradiotherapy (CRT) group, SA demonstrated significantly worse GCSS and OS for T1N1M0. There was no significant difference between CT and CRT in both T2N0M0 and T1N1M0 stages. T2N0M0 had a better survival than T1N1M0 in ELN ≤ 15 subgroup. However, similar survival was demonstrated in ELN > 15 subgroup.ConclusionsT2N0M0 GC has a better survival rate than T1N1M0 GC when ELN are ≤ 15. Moreover, T2N0M0 GC may not benefit from AT. T1N1M0 GC requires CT but not adjuvant radiotherapy.

VEGFR2 promotes tumorigenesis and metastasis in a pro-angiogenic-independent way in gastric cancer

BackgroundVEGF/VEGFR2 pathway is the central therapeutic target in anti-angiogenic treatment in multiple cancers. However, little work has been carried out concerning the pro-malignancy functions of VEGFR2 that are independent of its pro-angiogenesis effects in gastric cancer. Here, we demonstrated that VEGFR2 up-regulation in gastric cancer tissues was a prognostic marker for poor disease-free survival and overall survival of gastric cancer patients.MethodsImmunohistochemistry was used to detect VEGFR2 and VTN expressions in specimens. Kaplan–Meier curves were constructed for survival analysis. Stably knockdown cell lines and overexpression cell lines were constructed by small interfering RNA and plasmids transfection. Real-time PCR and Western blot were used to confirm the expressions of target genes at both RNA and protein levels. Cell proliferation was measured by using Cell Counting Kit-8 and xenograft models. Microarray and bioinformatic analysis were also performed to identify the relationship between Vitronectin (VTN) and VEGFR2.ResultsWhen overexpressed in gastric cancer cells, VEGFR2 increased cellular proliferation and invasion in vitro and tumor formation in xenograft models. By using integrating microarray and bioinformatic analysis, we identifiedVTN as a downstream of VEGFR2 pathway. In gain- and loss-of function analysis in gastric cancer cells, VTN was further verified in consistent with VEGFR2 in expression levels and in regulating cell growth and motility in vitro and in vivo. Moreover, in gastric cancer samples, VTN was as also revealed as a poor prognostic factor.ConclusionsOur present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects.ImplicationsOur present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects, which may provide a new and valuable target for design of therapies for intervention and a new cognitive perspective for the anti-angiogenesis therapies.

Lethal-7-related polymorphisms are associated with susceptibility to and prognosis of gastric cancer.

BACKGROUNDThe lethal-7 (let-7) family members and their targets are involved in the development and progression of tumors. Let-7-related polymorphisms have been reported to be associated with tumorigenesis and prognosis. In gastric cancer, however, the related studies are limited.AIMTo investigate the role of let-7-related microRNA polymorphisms in the tumorigenesis and prognosis of gastric cancer in a Chinese population.METHODSA total of 898 gastric cancer patients and 992 tumor-free controls were recruited into this study from 2008 to 2013. Gastric cancer patients were followed periodically. Ten single nucleotide polymorphisms (SNPs) in the let-7 gene region or their target mRNAs were genotyped using the MassARRAY system and their associations with the risk for or overall survival of gastric cancer were analyzed.RESULTSAll the ten SNPs were in Hardy-Weinberg equilibrium. The C allele of the rs3811463 polymorphism in the 3’-untranslated region (UTR) of LIN28A was associated with a lower risk of gastric cancer [odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.61-0.88, P = 0.001] after adjustment for age and Helicobacter pylori status. Seven hundred and thirty-five gastric cancer patients who had undergone radical tumorectomy were included in the survival analysis and their 5-year survival rate was 53.9% (95%CI: 50.1%-57.6%). The rs10889677 in the 3’-UTR of IL23R was corresponded to the prognosis of gastric cancer in a dose-response manner, in which the death risk increased by 25% [hazard ratio (HR) = 1.25, 95%CI: 1.04-1.45, P = 0.011] with each increase in the number of C alleles after controlling for other potential clinicopathological parameters.CONCLUSIONThe let-7-related polymorphism rs3811463 in LIN28A is associated with the susceptibility to gastric cancer and the let-7-related polymorphism rs10889677 in IL23R is associated with the prognosis of gastric cancer.

TCF7L1 indicates prognosis and promotes proliferation through activation of Keap1/NRF2 in gastric cancer.

Gastric cancer is one of the most common cancers worldwide and is the third leading cause of cancer-related deaths globally. Although significant progress has been made in the diagnosis and treatment for the cancer, less improvement has been made in overall survival rate. Thus, there is an urgent need for a better understanding of the biological aspects of the cancer. The transcription factor transcription factor 7-like 1 (TCF7L1) is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in gastric cancer has seldom been discussed. In the present study, by using the Cancer Genome Atlas dataset analysis, we demonstrated that patients with higher expression of TCF7L1 could be used to reflect prognosis. An examination of the mechanisms demonstrated that TCF7L1 could positively regulate antioxidant response in gastric cancer cells by positively regulating Keap1/NRF2 [Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2] pathway. Collectively, our data demonstrated that TCF7L1 is a novel marker for predicting overall survival of gastric cancer and provided the possible underlying molecular mechanism.

Prognostic values of inhibitory κB kinases mRNA expression in human gastric cancer.

Background: Inhibitory κB kinases (IKKs) play a key role in modulating proinflammatory and growth stimulating signals through their regulation of the nuclear factor κB (NF-κB) cascade. Therefore, the level of expression of IKKs represents a viable prognostic predictor with regard to various pathological processes. The prognostic value of IKKs expression in gastric cancer remains unclear. Methods: We used the ‘Kaplan–Meier plotter’ (KM plotter) online database, to explore the predictive prognostic value of individual IKKs members’ mRNA expression to overall survival (OS) in different clinical data including pathological staging, histology, and therapies employed. Results: Our results revealed that a higher mRNA expression of inhibitor of NF-κB kinase subunit α (IKKα) was correlated to better OS, whereas higher mRNA expression of IKKβ, inhibitor of NF-κB kinase subunit γ (IKKγ), inhibitor of NF-κB kinase subunit ε (IKKε), and suppressor of IKKε (SIKE) were generally correlated to unfavorable OS in gastric cancer. Increased mRNA expression of IKKε also showed better outcomes in stage IV gastric cancer. Further a correlation between elevated levels of mRNA expression of both IKKε and SIKE was found to have favorable OS in diffuse type gastric cancer. It was also revealed that high expression of SIKE had favorable OS when treated with other adjuvant therapies, while worse OS when treated only with 5FU therapy. Conclusion: Our results suggest that mRNA expression of individual IKKs and SIKE are associated with unique prognostic significance and may act as valuable prognostic biomarkers and potential targets for future therapeutic interventions in gastric cancer.

Expression of Demethylase Genes, FTO and ALKBH1, Is Associated with Prognosis of Gastric Cancer

BackgroundReversible N6-methyladenosine (m6A) modifications in messenger RNAs can be categorized under the field of “RNA epigenetics.” However, the potential role of m6A-related genes in gastric cancer (GC) prognosis has not been systematically researched.AimsThis study was aimed at providing insights into the prognostic role of m6A-related gene expression, at both mRNA and protein levels.MethodsKaplan–Meier (KM) plotter database and The Cancer Genome Atlas (TCGA) database were used to explore the prognostic significance of individual m6A-related genes in overall survival (OS) and progression-free survival at the mRNA level. For independent validation, the protein level of genes significantly associated with prognosis in both databases was further detected in 450 paired GC and corresponding adjacent non-tumor tissues using tissue microarray (TMA)-based immunohistochemistry (IHC). The relationship between the FTO and ALKBH1 expression and the clinicopathological characteristics was explored.ResultsAmong nine m6A-related genes, aberrantly high mRNA expression of FTO and ALKBH1 was associated with poor OS in the KM and TCGA cohorts. However, the TMA-IHC indicated that protein expression of FTO and ALKBH1 was markedly downregulated in GC tissues. A lower protein level of ALKBH1 was closely correlated with larger tumor sizes (≥ 5 cm) and more advanced TNM stages, while lower FTO protein expression was associated with shorter OS in GC patients.ConclusionsAberrant expression of demethylase genes, FTO and ALKBH1, has a distinct prognostic value in GC patients, indicating that FTO and ALKBH1 may play vital roles in GC progression and metastasis.

Association of RAGE gene four single nucleotide polymorphisms with the risk, invasion, metastasis and overall survival of gastric cancer in Chinese.

Objectives: The receptor for advanced glycation end products (RAGE) is an oncogenic trans-membranous receptor expressed in many cells. The aim of this study was to clarify the association between RAGE gene 4 single nucleotide polymorphisms (SNPs) and the risk, invasion, metastasis and overall survival of gastric cancer.Methods and Results: We performed a hospital-based case-control study involving 369 gastric cancer patients and 493 cancer free controls. Four widely-studied SNPs, rs1800625 (T-429C), rs1800624 (T-374A), rs2070600 (Gly82Ser) and rs184003 (G1704T) in RAGE gene, were genotyped by the polymerase chain reaction - ligase detection reaction method. The RAGE gene rs1800625 TT genotype and T allele were significantly associated with a reduced risk of gastric cancer (TT vs. CC: adjusted odds ratio [OR]: 0.72, 95% CI: 0.55-0.95, p=0.021; T vs. C: adjusted OR: 0.67, 95% CI: 0.46-0.97, p=0.032). No hints of significance were detected for the other three SNPs in association with gastric cancer risk. Moreover, rs1800625 and rs184003 were significantly associated with tumor clinical stage (p=0.010 and 0.032, respectively). Survival curves differed significantly between the genotypes of rs1800625.Conclusions: RAGE gene SNP rs1800625 was significantly associated with gastric cancer risk, and rs1800625 and rs184003 were related to tumor clinical stage, indicating that RAGE gene may be a gastric cancer-susceptibility gene.

Prognostic Value of XIAP Level in Patients with Various Cancers: A Systematic Review and Meta-Analysis.

Background: X-linked inhibitor of apoptosis protein (XIAP) plays an important role in cancer pathogenesis, which has been found to be overexpressed in multiple human cancers and associated with survival rates. Herein, we performed a meta-analysis to explore the predictive value of XIAP level in patients with various solid tumors.Methods: Relevant articles exploring the relationship between XIAP expression and survival of cancer patients were retrieved in PubMed, PMC, EMBASE and Web of Science published from 2001 to 2018. The combined hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the significance.Results: A total of 6554 patients from 40 articles were included in this meta-analysis. It was shown in 37 studies with 4864 cases that the over-expression of XIAP was associated with poorer overall survival (OS) (combined HR=1.61, 95% CI: 1.33-1.96). Meanwhile, 8 studies with 1862 cases revealed that elevated XIAP level predicted shorter disease-free survival (DFS) (HR=2.17, 95% CI: 1.03-4.59). Subgroup analyses showed that higher XIAP detection was related to worse OS in gastric cancer (HR=1.42, 95% CI: 1.18-1.72) and head and neck cancer (HNC) (HR=2.97, 95% CI: 1.97-4.47).Conclusion: Our results suggested that elevated XIAP level seemed to represent an unfavorable prognostic factor for clinical outcomes in cancer patients. However, there were limited studies describing the association between XIAP expression and clinical prognosis in each different type of tumors. Therefore, concrete roles of XIAP in various cancers need to be further explored.

Comprehensive Analysis of Aberrantly Expressed ceRNA network in gastric cancer with and without H.pylori infection

Objective: This study mainly focused on revealing ceRNA network in gastric cancer (GC) with Hp infection after comparing with GC without Hp infection and exploring the biological function and prognostic relevance of related molecules.Methods: The RNA expression profile data of GC patients with or without Hp infection were extracted from TCGA GDC data portal, including 20 GC cases with Hp infection and 168 GC cases without Hp infection. Differentially expressed lncRNAs, miRNAs and mRNAs were unveiled by package edgeR of R, and lncRNA-miRNA-mRNA ceRNA network was constructed by integrating the miRNA target information and the expression data of lncRNAs, miRNAs and mRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of aberrantly expressed mRNAs were performed to identify the related biological functions and pathologic pathways, and protein-protein interaction (PPI) network was constructed by STRING database. The overall survival (OS) of aberrantly expression lncRNAs and miRNAs were analyzed by package survival of R. A total of 30 gastric cancer tissues were used to validate the bioinformatics analysis results by real-time PCR.Results: Among the 32 differentially expressed miRNAs, 27 differentially expressed lncRNAs and 257 differentially expressed mRNAs were identified by comparing GC patients with and without Hp infection. Totally 10 miRNA, 11 lncRNA, 219 mRNA were included to build ceRNA network. GO and KEGG analysis revealed that differentially expressed mRNAs involved in the ceRNA network were mainly involved in extracellular exosomes, structural molecular activities, proteolysis and P13K-Akt signaling pathways. And PPI analysis obtained six hub genes of NTS, APOC3, OTX2, KRT13, CALCA, GNG4. Survival analysis showed that four lncRNAs (LINC01254, LINC01287, LINC01524, U95743.1) and four miRNAs (miR-302a, miR-302b, miR-1286, miR-378g) were associated with overall survival of GC with Hp infection. The real-time PCR results showed that, the levels of LINCO1254, LINCO1287, LINCO1524, U95743.1 were significantly higher in Hp positive GC patients than Hp negative patients (P=0.02, 0.048, 0.04, 0.036, respectively).Conclusion: Using TCGA database for data mining, we have successfully constructed a ceRNA regulatory network of GC with Hp infection, consisting of 10 lncRNAs, 11 miRNAs and 219 mRNAs. These findings might provide critical clues for the regulatory role of ceRNA network in the development of GC with Hp infection.

The prognostic potential of long noncoding RNA HOTAIR expression in human digestive system carcinomas: A meta-analysis.

Homeobox transcript antisense intergenic RNA (HOTAIR), one of the well-known long noncoding RNAs (lncRNAs), plays an important role in initiation and development of various tumors. Elevated level of HOTAIR is associated with metastatic behavior of primary tumor and poor outcome in several cancers. Therefore, we conducted a meta-analysis to clearly measure the prognostic impact of HOTAIR in patients with digestive system carcinomas. Fourteen studies including 2,666 patients with five different type of digestive system cancers were selected to be entered in meta-analysis. Finding demonstrated that HOTAIR overexpression could predict unfavorable outcome in digestive system carcinomas (hazard ratio [HR] = 2.4, 95% confidence interval [CI]: 2.0-2.9; p < 0.001; fixed-effect model). In stratified analysis, increased level of HOTAIR predicted poor overall survival in gastric cancer (HR = 2.1, 95% CI: 1.6-2.9; p < 0.001), colorectal cancer (HR = 4.1, 95% CI: 1.6-10.2; p = 0.002), esophageal squamous cell carcinoma (HR = 2.3, 95% CI: 1.7-3.0; p < 0.001), and hepatocellular carcinoma (HR = 3.4, 95% CI: 1.9-6.1; p < 0.001). Our meta-analysis results clearly support the prognostic value of HOTAIR to predict unfavorable prognostic outcomes in diverse digestive system carcinomas.

Development and validation of a prognostic signature for preoperative prediction of overall survival in gastric cancer patients.

BackgroundAs a serious challenge for public health, the prognosis of gastric cancer patients is still poor. The current study aimed to develop and validate a prognostic signature to predict the overall survival of gastric cancer patients.Patients and methodsThe dataset in the present study was obtained from The Cancer Genome Atlas database. The present study finally included 343 gastric cancer patients with information on long non-coding RNA (lncRNA) expression and overall survival.ResultsA prognostic model named Eleven-lncRNA signature was constructed according to the expression values of eleven prognostic lncRNA predictors identified by univariate and multivariate Cox regression model. According to time-dependent receiver operating characteristic curves, the Harrell’s concordance indexes of Eleven-lncRNA signature were 0.764 (95% CI 0.720–0.808), 0.776 (95% CI 0.732–0.820), and 0.807 (95% CI 0.763–0.851) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively in the model group. In the validation group, the Harrell’s concordance indexes of Eleven-lncRNA signature were 0.748 (95% CI 0.704–0.792), 0.794 (95% CI 0.750–0.838), and 0.798 (95% CI 0.754–0.842) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively. The gastric cancer patients (n=343) in the model group could be stratified into low-risk group (n=171) and high-risk group (n=172) according to the median of Eleven-lncRNA signature score. Kaplan–Meier survival curves showed that the mortality rate in the high-risk group was significantly poorer than that in the low-risk group (P<0.001).ConclusionThe present study constructed and validated a prognostic model named Eleven-lncRNA signature for preoperative individual mortality risk prediction in gastric cancer patients. This Eleven-lncRNA signature can predict the individual mortality risk of gastric cancer patients and is helpful in improving clinical decision making regarding individualized treatment.

Identification of discrepancy between CTLA4 expression and CTLA4 activation in gastric cancer

Objective: Recently, immune checkpoints blockers showed higher anti-tumor activity for advanced gastric cancer (GC). The purpose of the study is to find out predictive biomarkers related to anti-cytotoxic lymphocyte antigen 4 (CTLA4) therapy.Materials and methods: Datasets of gene expression omnibus (GEO), the cancer genome atlas (TCGA), and gene set enrichment analysis (GESA) were extracted. Differential expression of CTLA4 between cancer tissues and normal mucosa, enrichment of WT (wild type) vs. CTLA4_KO (knockout) upregulated gene set and clinical significance were analyzed. The expression of CTLA4, CD3, and granzyme A (GZMA) were validated on 30 cases of Chinese GC. Microsatellite instability (MSI) marker MLH1 and Epstein-Barr virus (EBV) marker EBER were examined on 30 cases of Chinese GC by immunohistochemistry and in situ hybridization.Results: CTLA4 was upregulated in GC tissue relative to normal mucosa in datasets of GSE27342 (fold change = 1.586, p < .001) and GSE63089 (fold change = 1.365, p < .001). Increased CTLA4 expression was positively related to CTLA4 activation. EBV-associated GC (EBVaGC) and microsatellite instability GC (MSIGC) disclosed higher CTLA4 levels than other GCs. Genomic stability GC (GSGC) also showed higher enrichment score of CTLA4 activation. CTLA4 activation resulted in shorter overall survival in GC. The expression level of CTLA4 was well correlated to expression levels of GZMA (R = 0.701, p < .001) and CD3 (R = 0.750, p < .001).Conclusions: Based on bioinformatics analysis, GSGC should be worth noticed as a potential GC subtypes responsive to anti-CTLA4 treatment.

KIF14 promotes tumor progression and metastasis and is an independent predictor of poor prognosis in human gastric cancer

The kinesin family member 14 (KIF14) is a potential oncogene and is involved in the metastasis of various cancers. Nevertheless, its function in gastric cancer (GC) remains poorly defined. The expression of KIF14 was examined in GC cell lines and a clinical cohort of GC specimens by qPCR, western blotting and immunohistochemistry (IHC) staining. The relationship between KIF14 expression and the clinicopathological features was analyzed. The effect of KIF14 on cell proliferation, colony formation, invasion and migration were investigated in vitro and in vivo. The expression of KIF14 was significantly increased in the GC tissues and cell lines. High KIF14 expression was associated with tumor stage, tumor-node-metastasis (TNM) stage and metastasis. KIF14 was an independent prognostic factor for the overall survival of GC, and a higher expression of KIF14 predicted a poorer survival. KIF14 silencing resulted in attenuated proliferation, invasion and migration in human gastric cancer cells, whereas KIF14 ectopic expression facilitated these biological abilities. Notably, the depressed expression of KIF14 inhibited Akt phosphorylation, while overexpressed KIF14 augmented Akt phosphorylation. Additionally, there was a significant correlation between the expression of KIF14 and p‑Akt in GC tissues. Importantly, the proliferation, invasion and migration of the GC cells, which was promoted by KIF14 overexpression, was abolished by the Akt inhibitor MK-2206, while Akt overexpression greatly rescued the effects induced by KIF14 knockdown. Our findings are the first to demonstrate that KIF14 is overexpressed in GC, is correlated with poor prognosis and plays a crucial role in the progression and metastasis of GC.

MicroRNA-495-3p inhibits multidrug resistance by modulating autophagy through GRP78/mTOR axis in gastric cancer

Multidrug resistance (MDR) accounts for poor prognosis in gastric cancer (GC). MicroRNAs (miRNAs) are critical regulators of MDR via modulation of the target genes. The present study revealed that miR-495-3p could act via a target gene, GRP78, to regulate the process of autophagy and inhibit MDR. Based on the in vitro and in vivo gain-of-function or loss-of-function experiments, overexpression of miR-495-3p was sufficient to reverse the MDR to four chemotherapeutics in vitro and inhibit the tumor growth in vivo. Moreover, GRP78 was positively associated with the occurrence of autophagy. Thus, reducing the expression of GRP78 by siRNA resulted in autophagy-suppressive activity similar to that of miR-495-3p on mammalian target of rapamycin (mTOR) and its substrates activation and autophagy inhibition, while restoring GRP78 attenuated the anti-autophagy effects caused by miR-495-3p. Clinically, either miR-495-3p downregulation or GRP78 upregulation was associated with malignant phenotypes in patients with GC. In conclusion, these findings demonstrate that miR-495-3p is an important regulator of autophagy balance and MDR by modulating the GRP78/mTOR axis. In addition, miR-495-3p and GRP78 could be used as prognostic factors for overall survival in GC, which implicates miR-495-3p as a therapeutic target in cancer.

The prognostic value of decreased NDRG1 expression in patients with digestive system cancers: A meta-analysis.

Background:Digestive system cancers are recognized as associated with high morbidity and mortality. It is generally accepted that N-myc downstream-regulated gene 1 (NDRG1) is aberrantly overexpressed or downregulated in digestive system cancers, and its prognostic value remains controversial. Accordingly, we herein conducted a meta-analysis to explore whether NDRG1 expression is correlated with overall survival (OS) and clinicopathological characteristics of patients with digestive system cancers.Methods:We systematically searched PubMed, EMBASE, and Web of Science for eligible studies up to June 6, 2017. In all, 19 publications with 21 studies, were included.Results:The pooled results showed that low NDRG1 expression was significantly associated with worse OS in colorectal cancer (pooled HR = 1.67, 95% CI: 1.22–2.28, P < .001) and pancreatic cancer (pooled HR = 1.87, 95% CI: 1–3.5, P < .0001). Moreover, the relationships between low NDRG1 expression and higher OS ratio of patients with liver cancer (pooled HR = 0.44, 95% CI: 0.32–0.62, P = .009) and gallbladder cancer (pooled HR = 0.56, 95% CI: 0.23–1.38, P = .01) were observed. Nevertheless, no significant association was observed between low NDRG1 expression and OS in gastric cancer (pooled HR = 0.81, 95% CI: 0.45–1.43, P = .46) or esophageal cancer (pooled HR = 0.76, 95% CI: 0.26–2.24, P = .62).Conclusion:The prognostic significance of NDRG1 expression varies according to cancer type in patients with DSCs. Considering that several limitations existed in this meta-analysis, more studies are required to further assess the prognostic value of NDRG1 expression in patients with DSCs and relevant mechanisms.

649P - The level of somatic mutations as an indicator of overall survival in gastric cancer

649P - The level of somatic mutations as an indicator of overall survival in gastric cancer

Superiority of the 8th edition of the TNM staging system for predicting overall survival in gastric cancer: Comparative analysis of the 7th and 8th editions in a monoinstitutional cohort.

The present study was performed to evaluate the predictive capacity of the 8th edition vs. the 7th edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for overall survival (OS) of patients with gastric cancer. Data of eligible patients with gastric cancer in our institution between June 2004 and June 2014 were retrospectively reviewed. A total of 1,506 patients were followed up to July 2016, among whom 1,484 patients with complete stage information were included in the TNM staging analysis. A total of 339 (22.8%) patients presented stage migration, including 325 (21.9%) migrating to a lower tier and 14 (0.9%) to a higher tier. All patients with stage migration to a lower tier were in stage III, including 177 (54.5%) patients migrating from stage IIIB to IIIA, and 148 (45.5%) from stage IIIC to IIIB. Patients migrating from IIIB to IIIA yielded a median OS time and 5-year OS rate closer to those remaining in stage IIIA. Similarly, patients migrating from IIIC to IIIB yielded a median OS time and 5-year OS rate closer to those remaining in stage IIIB. The 7th edition of the staging system exhibited prognostic discrepancy in discriminating stage IIIA from IIIB on survival curves, which was improved in the 8th edition. The 8th edition had a better predictive capability of survival, as evidenced by a smaller value of -2log likelihood in the Cox proportional regression model (7th edition 4738.859 vs. 8th edition 4736.683). Therefore, the present study demonstrated that the 8th edition of the AJCC TNM staging system is superior to the 7th edition in predicting the OS of patients with gastric cancer.