ERH Impacts Patient Prognosis and Tumor Immune Microenvironment: A Pan-Cancer Analysis.

BACKGROUND: The enhancer of rudimentary homolog (ERH) has been shown to play significant roles in tumorigenesis and progression. However, few systematic pan-cancer analyses about ERH have been described. METHODS: From the tumor immune estimation resource web server2.0 (TIMER2.0), the Genotype-Tissue Expression database (GTEx) and the Gene Expression Profile Interactive Analysis version 2 (GEPIA2) databases, we explored the expression profiles and prognostic significance of ERH in 33 cancers. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas (HPA) databases were further used to examine the differential expression of ERH at the protein level. The genetic alteration profile was obtained from the cBioPortal. The correlation between ERH expression and the quantities of immune infiltrating cells was examined by the TIMER tool. Spearman's correlation test was conducted to analyze the association between ERH expression status and a number of prognostic indicators, including immune checkpoints, TMB, MSI, immune neoantigen, MMR genes, and DNA methyltransferases. ProteinProtein Interaction analyses were performed in the String and GeneMANIA databases, and enrichment analysis and predicted signaling pathways were identified through GO and KEGG. To make our results convincing, we validated them in six datasets in the Gene Expression Omnibus (GEO) database. In addition, we verified the expression of ERH between gastric cancer tissues and adjacent normal tissues by RT-qPCR. RESULTS: ERH expression was elevated in numerous tumors, and it was not associated with the patient's prognosis. Furthermore, the quantities of immune infiltrating cells and immune checkpoint genes were remarkably associated with ERH. TMB and MSI were related to ERH expression in 14 and 15 cancer types, respectively. Moreover, the expression of ERH was strongly associated with MMR defects in multiple cancer types, and almost all tumors showed coexpression of ERH and four DNA methyltransferases. The results of GO and KEGG analysis confirmed that ERH potentially impacts several important signaling pathways. Both the GEO datasets and the RT-qPCR experiment validated our previous analysis. CONCLUSION: Our pan-cancer analysis demonstrated the characterization of ERH in multiple tumors. ERH may be a valuable novel biological indicator for assessing immunotherapy efficacy and prognosis in various malignancies.

Lifting the veils on transmembrane proteins: Potential anticancer targets.

Cancer, as a prevalent cause of mortality, poses a substantial global health burden and hinders efforts to enhance life expectancy. Nevertheless, the prognosis of patients with malignant tumors remains discouraging, owing to the lack of specific diagnostic and therapeutic targets. Therefore, the development of early diagnostic indicators and novel therapeutic drugs for the prevention and treatment of cancer is essential. Transmembrane proteins (TMEMs) are a class of proteins that can span the phospholipid bilayer and are stably anchored. They are associated with fibrotic diseases, neurodegenerative diseases, autoimmune diseases, developmental disorders, and cancer. It has been found that the expression levels of TMEMs were elevated or reduced in cancer cells, exerting pro/anticancer effects. These aberrant expression levels have also been linked to the prognostic and clinicopathological features of diverse tumors. In this review, the structures, functions, and roles of TMEMs in cancer were discussed, and the scientific perspectives were described. This review also explored the potential of TMEMs as tumor drug candidates from the perspective of targeted therapies, and the challenges that need to be overcome in a wide range of preclinical and clinical anticancer research were summarized.

TMEM200A is a potential prognostic biomarker and correlated with immune infiltrates in gastric cancer.

Background: Gastric cancer (GC) is one of the most common malignant tumors in the digestive system. Several transmembrane (TMEM) proteins are defined as tumor suppressors or oncogenes. However, the role and underlying mechanism of TMEM200A in GC remain unclear. Methods: We analyzed the expression of TMEM200A in GC. Furthermore, the influence of TMEM200A on survival of GC patients was evaluated. The correlations between the clinical information and TMEM200A expression were analyzed using chi-square test and logistic regression. Relevant prognostic factors were identified performing univariate and multivariate analysis. Gene set enrichment analysis (GSEA) was performed based on the TCGA dataset. Finally, we explore the relationship between TMEM200A expression and cancer immune infiltrates using CIBERSORT. Results: TMEM200A was up-regulated in GC tissues than that in adjacent non-tumor tissues based on TCGA database. Meta-analysis and RT-qPCR validated the difference in TMEM200A expression. Kaplan-Meier curves suggested the increased TMEM200A had a poor prognosis in GC patients. The chi-square test and logistic regression analyses showed that the TMEM200A expression correlates significantly with T stage. Multivariate analysis showed that TMEM200A expression might be an important independent predictor of poor overall survival in GC patients. GSEA identified five immune-related signaling pathways and five tumor-related signaling pathways significantly enriched in the high TMEM200A expression phenotype pathway. Finally, we found CD8+ T cells is apparently decreased in high TMEM200A expression group. Conversely, eosinophils is increased in high expression group compared with low expression group. Conclusion: TMEM200A is a potential prognostic biomarker and correlated with immune infiltrates in GC.

A prognostic signature of pyroptosis-related lncRNAs verified in gastric cancer samples to predict the immunotherapy and chemotherapy drug sensitivity.

Background: Pyroptosis is a recently identified mode of programmed inflammatory cell death that has remarkable implications for cancer development. lncRNAs can be involved in cellular regulation through various pathways and play a critical role in gastric cancer (GC). However, pyroptosis -related lncRNAs (PRlncRNAs) have been rarely studied in GC. Methods: Pyroptosis-related gene were abstracted from the literature and GSEA Molecular Signatures data resource. PRlncRNAs were obtained using co-expression analysis. LASSO Cox regression assessment was employed to build a risk model. Kaplan-Meier (KM), univariate along with multivariate Cox regression analysis were adopted to verify the predictive efficiency of the risk model in terms of prognosis. qRT-PCR was adopted to validate the expression of PRlncRNAs in GC tissues. In addition, immune cell infiltration assessment and ESTIMATE score evaluation were adopted for assessing the relationship of the risk model with the tumor immune microenvironment (TME). Finally, immune checkpoint gene association analysis and chemotherapy drug sensitivity analysis were implemented to assess the worthiness of our risk model in immunotherapy and chemotherapy of GC. Results: We identified 3 key PRlncRNAs (PVT1, CYMP-AS1 and AC017076.1) and testified the difference of their expression levels in GC tumor tissues and neighboring non-malignant tissues (p < 0.05). PRlncRNAs risk model was able to successfully estimate the prognosis of GC patients, and lower rate of survival was seen in the high-GC risk group relative to the low-GC risk group (p < 0.001). Other digestive system tumors such as pancreatic cancer further validated our risk model. There was a dramatic difference in TMB level between high-GC and low-GC risk groups (p < 0.001). Immune cell infiltration analysis and ESTIMATE score evaluation demonstrated that the risk model can be adopted as an indicator of TME status. Besides, the expressions of immunodetection site genes in different risk groups were remarkably different (CTLA-4 (r = -0.14, p = 0.010), VISTA (r = 0.15, p = 0.005), and B7-H3 (r = 0.14, p = 0.009)). PRlncRNAs risk model was able to effectively establish a connection with the sensitivity of chemotherapeutic agents. Conclusion: The 3 PRlncRNAs identified in this study could be utilized to predict disease outcome in GC patients. It may also be a potential therapeutic target in GC therapy, including immunotherapy and chemotherapy.

Hsa_circ_0044301 Regulates Gastric Cancer Cell's Proliferation, Migration, and Invasion by Modulating the Hsa-miR-188-5p/DAXX Axis and MAPK Pathway.

Background: Despite advances in diagnostic and therapeutic technologies, the prognosis of patients with gastric cancer (GC) remains poor, necessitating further search for more effective therapeutic targets and markers for prognosis prediction. Circular RNA (circRNA) plays a role in various diseases, including GC. Methods: CircRNA expression in GC tissues was detected by circRNA microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The correlation between circRNA-0044301 and patient survival was analyzed by log-rank test and Cox regression analysis. Next, in vitro characterization and functional analysis of circRNA-0044301 was done by various assays using RNase R, actinomycin D, and RNA fluorescence in situ hybridization, as well as investigations into its use as a drug to treat tumors in a subcutaneous tumorigenesis model. RNA immunoprecipitation and dual-luciferase reporter assays were used to identify circRNA-0044301-related miRNA (miRNA-188-5p), key proteins of the related pathway (ERK1/2), and the downstream target DAXX. Finally, we investigated the relationship between circRNA-0044301 and ravoxertinib (GDC-0994) and 5-fluorouracil (5-FU) using qRT-PCR, Western blotting, and CCK8 assays. Results: CircRNA-0044301 was upregulated in tissues and cancer cells compared to its levels in controls, related to patient prognosis, and its specific siRNA-vivo could slow tumor growth. On the mechanism, it acted as a sponge of miRNA-188-5p, could regulate the downstream target DAXX, and modulated the effect of GDC-0994 on ERK1/2 and 5-FU in cells. Conclusions: CircRNA-0044301/miRNA-188-5p/DAXX (ERK1/2) may be a key axis in GC progression, and circRNA-0044301 has immense potential to be a therapeutic target for GC.

Helicobacter pylori CagA Protein Regulating the Biological Characteristics of Gastric Cancer through the miR-155-5p/SMAD2/SP1 axis.

Helicobacter pylori (Hp) is a grade Ι carcinogen of gastric cancer (GC), and its high infection rate seriously affects human health. Cytotoxin-associated gene A (CagA) plays a key role in the carcinogenesis of Hp as one of its main virulence factors. miR-155-5p is abnormally expressed in patients with GC, associated with the occurrence and development of cancer. However, little is known about the association between CagA and miR-155-5p. (1) Background: This study explored the association and mechanism of CagA and miR-155-5p in GC. (2) Methods: The CagA sequence was obtained from the NCBI. After sequence optimization, it was connected to the pcDNA3.1 vector to construct a CagA eukaryotic expression plasmid (pcDNA-CagA). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to investigate the expression of miR-155-5p and CagA in GC cells. The function of CagA on GC cells was detected by CCK8, wound healing, and Transwell assays. Similarly, the function of miR-155-5p was also studied through the above functional experiments after the miR-155-5p overexpression and knockdown models had successfully been constructed. The associations among CagA, miR-155-5p, and SMAD2/SP1 were evaluated using RNA immunoprecipitation (RIP) and rescue experiments. (3) Results: The expression of miR-155-5p was significantly reduced in GC cells, and the expression of miR-155-5p was further reduced after CagA induction. Both overexpressed CagA and knockdown miR-155-5p cell models enhanced malignant transformation, whereas overexpressed miR-155-5p inhibited malignant transformation in vitro. The function of miR-155-5p on GC cells could be influenced by CagA. We also found that the influence of miR-155-5p on SMAD2 and SP1 could be regulated by CagA. (4) Conclusions: CagA potentially regulates the biological function of GC cells through the miR-155-5p/SMAD2/SP1 axis. miR-155-5p could be a therapeutic target for GC related to CagA.

Identification and Validation of an m6A Modification of JAK-STAT Signaling Pathway-Related Prognostic Prediction Model in Gastric Cancer.

Background: Gastric cancer (GC) is one of the malignant tumors worldwide. Janus (JAK)-signal transduction and activator of transcription (STAT) signaling pathway is involved in cellular biological process and immune function. However, the association between them is still not systematically described. Therefore, in this study, we aimed to identify key genes involved in JAK-STAT signaling pathway and GC, as well as the potential mechanism. Methods: The Cancer Genome Atlas (TCGA) database was the source of RNA-sequencing data of GC patients. Gene Expression Omnibus (GEO) database was used as the validation set. The predictive value of the JAK-STAT signaling pathway-related prognostic prediction model was examined using least absolute shrinkage and selection operator (LASSO); survival, univariate, and multivariate Cox regression analyses; and receiver operating characteristic curve (ROC) analyses to examine the predictive value of the model. Quantitative real-time polymerase chain reaction (qRT-PCR) and chi-square test were used to verify the expression of genes in the model and assess the association between the genes and clinicopathological parameters of GC patients, respectively. Then, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis, version 3.0 (GSEA), sequence-based RNA adenosine methylation site predictor (SRAMP) online websites, and RNA immunoprecipitation (RIP) experiments were used to predict the model-related potential pathways, m6A modifications, and the association between model genes and m6A. Results: A four-gene prognostic model (GHR, PIM1, IFNA8, and IFNB1) was constructed, namely, riskScore. The Kaplan-Meier curves suggested that patients with high riskScore expression had a poorer prognosis than those with low riskScore expression (p = 0.006). Multivariate Cox regression analyses showed that the model could be an independent predictor (p < 0.001; HR = 3.342, 95%, CI = 1.834-6.088). The 5-year area under time-dependent ROC curve (AUC) reached 0.655. The training test set verified these results. Further analyses unveiled an enrichment of cancer-related pathways, m6A modifications, and the direct interaction between m6A and the four genes. Conclusion: This four-gene prognostic model could be applied to predict the prognosis of GC patients and might be a promising therapeutic target in GC.

The Role of SETBP1 in Gastric Cancer: Friend or Foe.

Background: Gastric cancer (GC) remains a common disease with a poor prognosis worldwide. The SET binding protein 1 (SETBP1) has been implicated in the pathogenesis of several cancers and plays a dual role as an oncogene and a tumor suppressor gene. However, the role and underlying mechanism of SETBP1 in GC remain unclear. Materials and Methods: We used next-generation RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) to explore the correlation between SETBP1 expression and tumor progression. We then quantified SETBP1 expression in GC cells with real-time quantitative polymerase chain reactions (RT-qPCR). The chi-square test and logistic regression were used to assess the correlation between SETBP1 expression and clinicopathological features. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to assess the relationship between SETBP1 expression and survival. Finally, gene set enrichment analyses (GSEA) were used to examine GC-related signaling pathways in low and high SETBP1 expressing samples. Results: We found SETBP1 expression levels in GC tissues to be significantly lower than in adjacent non-tumor tissues in the TCGA database. In addition, SETBP1 expression differed significantly between groups classified by tumor differentiation. Furthermore, SETBP1 expression in diffuse-type GC was significantly higher than in intestinal-type GC. However, it did not differ significantly across pathological- or T-stage groups. RT-qPCR and comprehensive meta-analysis showed that SETBP1 expression is downregulated in GC cells and tissues. Interestingly, SETBP1 expression in poorly- or un-differentiated GC cells was higher than in well-differentiated GC cells. Moreover, the chi-square test and logistic regression analyses showed that SETBP1 expression correlates significantly with tumor differentiation. Kaplan-Meier curves indicated that patients with relatively high SETBP1 expression had a poor prognosis. Multivariate analyses indicated that SETBP1 expression might be an important predictor of poor overall survival in GC patients. GSEA indicated that 20 signaling pathways were significantly enriched in samples with high and low SETBP1 expression. Conclusion: SETBP1 may play a dual role in GC progression.

Hsa_circ_0000081 promotes the function of gastric cancer through sponging hsa-miR-423-5p to influence 3-phosphoinositide-dependent kinase 1 expression.

Gastric cancer (GC) is one of the most common malignancies in the world, and effective therapeutic targets need to be identified for this type of cancer. In this study, circular RNA (circRNA) microarray analysis was utilized to screen differentially expressed circRNA in GC. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR), hsa_circ_0000081 (circRNA-0000081) expression was found to be up-regulated in tissues and cells and was negative correlated with patients' survival time. RNase R and Actinomycin D assays indicated that circRNA-0000081 was significantly more resistant to R enzyme and had a longer half-life than linear RNA. Moreover, the knockdown or overexpression of circRNA-000081 could influence the proliferation, migration, and invasion potential of GC. Finally, dual luciferase reporter, RNA immunoprecipitation, qRT-PCR, and western blotting assays were used to verify the targeting relationship between circRNA-000081 and miRNA-423-5p or miRNA-423-5p and 3-phosphoinositide-dependent kinase 1 (PDPK1). In conclusion, circRNA-0000081 promotes the function of GC through sponging hsa-miR-423-5p to influence PDPK1 expression, which has a promising therapeutic potential for treating patients with GC.

The tumor immune-microenvironment in gastric cancer.

AIMS AND BACKGROUND: The tumor microenvironment significantly influences malignant behavior and progression. Many components are involved in the tumor microenvironment, including extracellular matrix, stromal cells, immune and inflammatory cells, as well as cytokines that promote tumor development with complex interactions through the exchange of molecular information. It is now known that tumor immune escape may be influenced by the tumor microenvironment. The aim of this work is to conduct a review of the tumor immune-microenvironment in gastric cancer. METHODS: We review the current knowledge of several immune cells involved in the gastric tumor microenvironment. In addition, a brief description of immunotherapy strategies for gastric cancer is also reviewed. CONCLUSIONS: Among immune cell populations, lymphocytes, macrophages, dendritic cells and myeloid-derived suppressor cells are revealed to make the difference in promoting or suppressing gastric tumorigenesis, either directly or indirectly, via regulating the immune responses. Understanding these interactions in detail within the tumor immune-microenvironment will contribute to unraveling new therapeutic targets.

Overexpression of GUCY1A2 Correlates With Poor Prognosis in Gastric Cancer Patients.

BACKGROUND: Nitric oxide (NO) and cyclic guanosine phosphate (cGMP) play important roles in blood pressure regulation, neurotransmitter delivery, renal function, and tumorigenesis and development. The intermediate link of this signaling pathway, soluble guanylyl cyclase (sGC), is particularly important. However, the role of the GUCY1A2 gene encoding the sGC α2 subunit is unknown. METHODS: Gene expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. After screening for GUCY1A2 expression, the expression differences between gastric cancer (GC) tissues and adjacent noncancerous tissues were determined using R software. Quantitative real-time polymerase chain reaction (qRT-PCR) and meta-analysis were used to verify the result. The correlation between the expression of GUCY1A2 and clinicopathological parameters was explored by logistic regression. Then, Kaplan-Meier survival analysis and the Cox proportional hazards regression were used to evaluate the relationship between the expression of GUCY1A2 and the survival of GC patients. Finally, gene set enrichment analysis (GSEA) was used to explore and analyze the GC-related signaling pathways affected by high GUCY1A2 expression. RESULTS: We found that GUCY1A2 was highly expressed in GC tissues compared to adjacent noncancerous tissues (P < 0.001). qRT-PCR (P < 0.001) and meta-analysis (SMD = 0.65, 95% CI: 0.20-1.10) confirmed the difference in GUCY1A2 expression. Logistic regression analysis showed that high expression of GUCY1A2 was associated with histological grade (OR=1.858 for poor vs. well or moderate, P = 0.004) and T stage (OR = 3.389 for T3 vs. T1, P = 0.025; OR = 3.422 for T4 vs. T1, P = 0.028). Kaplan-Meier curves indicated that GC patients with high expression of GUCY1A2 had a poor prognosis than that of patients with low expression. Univariate analysis indicated that GUCY1A2 and some clinicopathological parameters, such as age, pathological stage, and TNM stage, may predict poor prognosis. Multivariate analysis further confirmed that GUCY1A2 was an independent prognostic marker (HR = 1.699; 95%CI, 1.175-2.456; P = 0.005). GSEA showed that the high GUCY1A2 phenotype is significantly enriched for tumor-associated signaling pathways. CONCLUSIONS: GUCY1A2 is highly expressed in GC and may be used as a potential prognostic marker.

Prognostic Prediction Using a Stemness Index-Related Signature in a Cohort of Gastric Cancer.

BACKGROUND: With characteristic self-renewal and multipotent differentiation, cancer stem cells (CSCs) have a crucial influence on the metastasis, relapse and drug resistance of gastric cancer (GC). However, the genes that participates in the stemness of GC stem cells have not been identified. METHODS: The mRNA expression-based stemness index (mRNAsi) was analyzed with differential expressions in GC. The weighted gene co-expression network analysis (WGCNA) was utilized to build a co-expression network targeting differentially expressed genes (DEG) and discover mRNAsi-related modules and genes. We assessed the association between the key genes at both the transcription and protein level. Gene Expression Omnibus (GEO) database was used to validate the expression levels of the key genes. The risk model was established according to the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Furthermore, we determined the prognostic value of the model by employing Kaplan-Meier (KM) plus multivariate Cox analysis. RESULTS: GC tissues exhibited a substantially higher mRNAsi relative to the healthy non-tumor tissues. Based on WGCNA, 17 key genes (ARHGAP11A, BUB1, BUB1B, C1orf112, CENPF, KIF14, KIF15, KIF18B, KIF4A, NCAPH, PLK4, RACGAP1, RAD54L, SGO2, TPX2, TTK, and XRCC2) were identified. These key genes were clearly overexpressed in GC and validated in the GEO database. The protein-protein interaction (PPI) network as assessed by STRING indicated that the key genes were tightly connected. After LASSO analysis, a nine-gene risk model (BUB1B, NCAPH, KIF15, RAD54L, KIF18B, KIF4A, TTK, SGO2, C1orf112) was constructed. The overall survival in the high-risk group was relatively poor. The area under curve (AUC) of risk score was higher compared to that of clinicopathological characteristics. According to the multivariate Cox analysis, the nine-gene risk model was a predictor of disease outcomes in GC patients (HR, 7.606; 95% CI, 3.037-19.051; P < 0.001). We constructed a prognostic nomogram with well-fitted calibration curve based on risk score and clinical data. CONCLUSION: The 17 mRNAsi-related key genes identified in this study could be potential treatment targets in GC treatment, considering that they can inhibit the stemness properties. The nine-gene risk model can be employed to predict the disease outcomes of the patients.

LUM Expression and Its Prognostic Significance in Gastric Cancer.

Background: Lumican (LUM) is a member of the small leucine-rich proteoglycan family and plays dual roles as an oncogene and a tumor suppressor gene. The effect of LUM on tumors is still controversial. Methods: Gene expression profiles and clinical data of gastric cancer (GC) were downloaded from The Cancer Genome Atlas (TCGA) database. The expression difference of LUM in GC tissues and adjacent nontumor tissues was analyzed by R software and verified by quantitative real-time polymerase chain reaction (qRT-PCR) and comprehensive meta-analysis. The relationship between LUM expression and clinicopathological parameters was assessed by chi-square test and logistic regression. Kaplan-Meier survival analysis and Cox proportional hazards regression model were chosen to assess the effect of LUM expression on survival. Gene set enrichment analysis (GSEA) was used to screen the signaling pathways involved in GC between the low and the high LUM expression datasets. Results: The expression of LUM in GC tissues was significantly higher than that in adjacent nontumor tissues (P < 0.001) from the TCGA database. qRT-PCR (P = 0.022) and comprehensive meta-analysis (standard mean difference = 0.90, 95% CI: 0.34-1.46) demonstrated that LUM was upregulated in GC. The chi-square test showed that the high expression of LUM was correlated with tumor differentiation (P = 0.024) and T stage (P = 0.004). Logistic regression analysis showed that high LUM expression was significantly correlated with tumor differentiation (OR = 1.543 for poor vs. well or moderate, P = 0.043), pathological stage (OR = 3.149 for stage II vs. stage I, P = 0.001; OR = 2.505 for stage III vs. stage I, P = 0.007), and T classification (OR = 13.304 for T2 vs. T1, P = 0.014; OR = 18.434 for T3 vs. T1, P = 0.005; OR = 30.649 for T4 vs. T1, P = 0.001). The Kaplan-Meier curves suggested that patients with high LUM expression had a poor prognosis. Multivariate analysis showed that a high expression of LUM was an important independent predictor of poor overall survival (HR, 1.189; 95% CI, 1.011-1.400; P = 0.037). GSEA indicated that 14 signaling pathways were evidently enriched in samples with the high-LUM expression phenotype. Conclusions: LUM might act as an oncogene in the progression of GC and could be regarded as a potential prognostic indicator and therapeutic target for GC.

CYP2E1 changes the biological function of gastric cancer cells via the PI3K/Akt/mTOR signaling pathway.

The present study investigated the role of cytochrome P450 family 2 subfamily E polypeptide 1 (CYP2E1) in the development and progression of gastric cancer (GC). The expression levels of CYP2E1 in MGC­803 GC cells and normal GES­1 cells were investigated via western blotting, and it was identified that the expression of CYP2E1 was different between GES­1 and MGC­803 cells. CYP2E1 was overexpressed in MGC­803 cells using a lentiviral vector GV358. Cell Counting Kit­8, flow cytometry, cell migration and Matrigel invasion assays suggested that overexpression of CYP2E1 promoted the proliferation and invasion, and inhibited the apoptosis of GC cells. The relationship between CYP2E1 expression and key signaling molecules in the PI3K/Akt/mTOR signaling pathway was assessed. Reverse transcription­quantitative PCR analysis showed that mTOR mRNA expression was significantly increased after overexpression of CYP2E1 (P<0.05). Western blotting results showed that overexpression of CYP2E1 upregulated the expression of phosphorylated (p)­Akt, p­mTOR and p­p70 ribosomal protein S6 kinase (P70S6K; Ser371) proteins (P<0.05). To further investigate the relationship between CYP2E1 and the PI3K/Akt/mTOR signaling pathway in GC cells, MGC­803 cells were treated with the PI3K inhibitor LY294002, and changes in the expression levels of PI3K, AKT, mTOR, P70S6K and CYP2E1 were observed. The present results showed that LY294002 downregulated the expression of PI3K, CYP2E1, AKT, mTOR and P70S6K (P<0.05). Therefore, changes in the biological function of GC cells induced by CYP2E1 overexpression may be via the PI3K/Akt/mTOR signaling pathway.

Current prevalence status of gastric cancer and recent studies on the roles of circular RNAs and methods used to investigate circular RNAs.

Gastric cancer is a malignant tumor with the fifth incidence and third mortality worldwide. There were 951,000 new cases and about 723,000 patients died of it in 2012. Undoubtedly, gastric cancer has been affecting people's living standards, and is already a major public health problem in China with its population growth and ageing. Even though the detection methods and medical standards have improved, the five-year survival rate of people is still very low. While circular RNA (circRNA) is increasingly attracting attention from researchers, at the same time, its mystery has gradually been uncovered. Many studies have shown that circRNA can act as molecular sponge of miRNA to regulate gene expression and has an obviously different expression profile between cancerous and normal groups, which arouse people's curiosity and provide new opportunities for early detection of gastric cancer to improve the quality of life of patients. This study reviews current prevalence of gastric cancer in the word and China, as well as the characteristics and functions of circRNA and common laboratory detection methods involving circRNA in gastric cancer.

Circular RNAs as diagnostic biomarkers in gastric cancer: A meta-analysis review.

PURPOSE: Gastric cancer is a malignant tumor in the world and circRNA has a close connection with it. However, the effects of circRNA on gastric cancer is still not clear. METHODS: A comprehensive search of PubMed, Web of Science and Embase for published experimental studies about circRNA from 2013 to June 2018 was conducted with two investigators. Diagnostic OR (DOR) was calculated to evaluate the diagnostic efficacy by STATA 12.0. RESULTS: Total 11 studies were found, including 12 kinds of circRNAs, 11 in tissues, 5 in plasma, and all down regulated. The combined DOR and AUC (Area Under the Curve of Receiver Operating Characteristic) with their 95%CI were 8.778 [6.108, 12.614] and 0.81 [0.78, 0.84] respectively, indicating that circRNAs can reflect gastric cancer as well. Subgroup analysis revealed that circRNAs in plasma were higher than tissues as well as in subgroup with different sample sizes. We speculated that the heterogeneity of the literatures was mainly due to the different backgrounds of gastric cancer and the differences in experimental design and operation process. And the Deeks' funnel map revealed there was no obvious public biasness in the literature. CONCLUSION: CircRNAs have high sensitivity and specificity in the diagnosis of gastric cancer, and it may become an auxiliary diagnostic biomarker of gastric cancer.

Associations of PIK3CA mutations with clinical features and prognosis in gastric cancer.

Aim: The clinical implications of PIK3CA mutations in gastric cancer (GC) are not conclusive. Materials & methods: A systematic searching of the previous publications and related studies in The Cancer Genome Atlas (TCGA) database were performed to investigate the clinical implications of PIK3CA mutations in GC.  Results: Twenty-six independent cohort studies including six studies with original data were identified. Meta-analysis suggested PIK3CA mutations were associated with high T stage, poor differentiation and microsatellite instability, but not with prognosis in overall. However, PIK3CA mutation was found to be associated with favorable overall survival in subgroup of patients with low PIK3CA mutation prevalence. Conclusion: PIK3CA mutations might be involved in GC development and might be used as favorable prognostic factor in GC population with low PIK3CA mutations prevalence.

Association of sirtuins with clinicopathological parameters and overall survival in gastric cancer.

To evaluate the associations of sirtuins (SIRT1-7) with clinicopathological parameters in gastric cancer, sirtuins expression profile in NCBI GEO datasets, GSE62254 and GSE15459, was integrated and analyzed. The results suggested that SIRT4, SIRT6, and SIRT7 were associated with Lauren classification and SIRT3-5 were associated with pStage in gastric cancer. Then an online database derived from 1,065 gastric cancer cases, Kaplan-Meier plotter, was used to explore the associations of the mRNA levels of sirtuins with overall survival in gastric cancer. Survival curves generated from Kaplan-Meier plotter suggested that high expression of SIRT1 mRNA was favorable for overall survival in gastric cancer (SIRT1: HR = 0.64, 95% CI = 0.54-0.76, P = 2.2E-07), high expressions of SIRT2-4 and SIRT6-7 were poor for overall survival (SIRT2: HR = 2.31, 95% CI = 1.87-2.87, P = 3.6E-15; SIRT3: HR = 1.99, 95% CI = 1.62-2.45, P = 2.6E-11; SIRT4: HR = 1.41, 95% CI = 1.19-1.68, P = 6.6E-05; SIRT6: HR = 2.02, 95% CI = 1.66-2.47, P = 1.7E-12; SIRT7: HR = 1.96, 95% CI = 1.63-2.35, P = 2.7E-13), whereas no significant association existed between SIRT5 mRNA expression and overall survival. Further analyses stratified by gender, stages, Lauren classification, differentiation, treatment, and HER2 status were also performed. In summary, high SIRT1 mRNA level was associated with better overall survival, SIRT2-4 and 6-7 were associated with poor overall survival, whereas SIRT5 did not show significant association with overall survival in gastric cancer.

Predictive value of GSTP1 Ile105Val polymorphism in clinical outcomes of chemotherapy in gastric and colorectal cancers: a systematic review and meta-analysis.

PURPOSE: Gastric and colorectal cancers remain the major causes of cancer-related death with a bad prognosis. Up to now, platinum combined with fluoropyrimidines has been most commonly used in chemotherapy regimens of gastric and colorectal cancers. Recently, a series of studies have been conducted to investigate the associations of biomarkers, such as GSTP1 Ile105Val polymorphism, with the chemotherapy efficacy in gastric and colorectal cancers; however, the results were not consistent and inconclusive. Here, we performed a systematic review and meta-analysis to summarize the associations of GSTP1 Ile105Val polymorphism with the chemotherapy efficacy in gastric and colorectal cancers. METHODS: A systematic review was conducted to search relevant studies in English databases (PubMed, ISI Web of Science, and EMBASE) up to November 30, 2015. The pooling ORs or HRs were used to assess the strength of the associations of GSTP1 Ile105Val polymorphism with clinical outcomes such as tumor response, toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Forty-one papers containing 8169 cases were finally included in the present meta-analysis study. Of which, 28 articles were performed in colorectal cancers, one in gastrointestinal carcinoma (gastric and colon cancer), 11 in gastric cancers, and one in colorectal and gastroesophageal cancers. After pooling all the eligible studies, we identified significant associations of GSTP1 Ile105Val polymorphism with chemotherapy-related tumor response (G vs. A: OR 1.697, 95 % CI 1.191-2.418; GG vs. AA: OR 2.804, 95 % CI 1.414-5.560; AG vs. AA: OR 1.540, 95 % CI 1.011-2.347; GG vs. AAAG: OR 2.139, 95 % CI 1.256-3.641), PFS (GG vs. AA, HR 0.640, 95 % CI 0.455-0.900; AGGG vs. AA: HR 0.718, 95 % CI 0.562-0.919), and OS (AG vs. AA: HR 0.857, 95 % CI 0.746-0.986; GG vs. AA: HR 0.679, 95 % CI 0.523-0.882; AGGG vs. AA: HR 0.663, 95 % CI 0.542-0.812) in gastric and colorectal cancers and no significant association was found between the polymorphism with toxicity. CONCLUSIONS: GSTP1 Ile105Val polymorphism was associated with tumor response, PFS, and OS in gastric and colorectal cancers after chemotherapy.

Screening of susceptibility genes and multi-gene risk analysis in gastric cancer.

The aim of the study was to explore the relations between the genetic polymorphism and the susceptibility to the gastric cancer in Chinese Han population, and to analyze the multi-genes risk in the development of gastric carcinoma. A case-control study of 1:1 matching was performed on 564 individuals with primary gastric carcinoma in Nanjing, China. The genotypes of CYP2E1, GSTMl, GSTTl, NAT2, ALDH2, MTHFR, XRCCl, IL-1ß, VDR, and TNF were detected by molecular biological techniques (PCR-RFLP and AS-PCR). Sole gene and gene-gene interactions were analyzed using Logistic regression model. The effect of multi-genes on gastric carcinoma was analyzed using multi-gene risk analysis model, which focused on the effect of multi-gene interaction on the development of gastric carcinoma. The genotypes involved in the susceptibility of gastric carcinoma were CYP2E1(c1/c1), NAT2M1(T/T), NAT2M2(A/A), XRCC1194(T/T), NAT2 phenotype (slow acetylator), MTHFR1298(A/C), and VDR TaqI(T/T), respectively. Multi-gene risk analysis model was introduced to analyze the effect of these genes on the gastric carcinoma. The results showed that there was a strong relation between odds ratio (OR) value of polygene combination and the gene frequency. With the increase of susceptibility gene frequency, the risk distribution curve of gastric carcinoma would shift to a more dangerous phase and exhibit a quantitative relation. Our results demonstrated that the OR of each gene can be utilized as an index to assess the effect of multiple susceptible genes on the occurrence of gastric carcinoma.