Gastric cancer is the third deadliest cancer in the world and ranks second in incidence and mortality of cancers in China. Despite advances in prevention, diagnosis, and therapy, the absolute number of cases is increasing every year due to aging and the growth of high-risk populations, and gastric cancer is still a leading cause of cancer-related death. Gastric cancer is a consequence of the complex interaction of microbial agents, with environmental and host factors, resulting in the dysregulation of multiple oncogenic and tumor-suppressing signaling pathways. Global efforts have been made to investigate in detail the genomic and epigenomic heterogeneity of this disease, resulting in the identification of new specific and sensitive predictive and prognostic biomarkers. Trastuzumab, a monoclonal antibody against the HER2 receptor, is approved in the first-line treatment of patients with HER2+ tumors, which accounts for 13%-23% of the gastric cancer population. Ramucirumab, a monoclonal antibody against VEGFR2, is currently recommended in patients progressing after first-line treatment. Several clinical trials have also tested novel agents for advanced gastric cancer but mostly with disappointing results, such as anti-EGFR and anti-MET monoclonal antibodies. Therefore, it is still of great significance to screen specific molecular targets for gastric cancer and drugs directed against the molecular targets.

To investigate the effect and mechanism of berberine against tumor growth in gastric cancer xenograft models and to explore the role of hepatocyte nuclear factor 4α (HNF4α)-WNT5a/β-catenin pathways played in the antitumor effects of berberine.

MGC803 and SGC7901 subcutaneous xenograft models were established. The control group was intragastrically administrated with normal saline, and the berberine group was administrated intragastrically with 100 mg/kg/d berberine. The body weight of nude mice during the experiment was measured to assess whether berberine has any adverse reaction. The volume of subcutaneous tumors during this experiment was recorded to evaluate the inhibitory effect of berberine on the growth of MGC803 and SGC7901 subcutaneous transplantation tumors. Polymerase chain reaction assays were conducted to evaluate the alteration of transcriptional expression of HNF4α, WNT5a and β-catenin in tumor tissues and liver tissues from the MGC803 and SGC7901 xenograft models. Western blotting and IHC were performed to assess the protein expression of HNF4α, WNT5a and β-catenin in tumor tissues and liver tissues from the MGC803 and SGC7901 xenograft models.

In the both MGC803 and SGC7901 xenograft tumor models, berberine significantly reduced tumor volume and weight and thus retarded the growth rate of tumors. In the SGC7901 and MGC803 subcutaneously transplanted tumor models, berberine down-regulated the expression of HNF4α, WNT5a and β-catenin in tumor tissues from both transcription and protein levels. Besides, berberine also suppressed the protein expression of HNF4α, WNT5a and β-catenin in liver tissues.

Berberine retarded the growth of MGC803 and SGC7901 xenograft model tumors, and the mechanism behind these anti-growth effects might be the downregulation of the expression of HNF4α-WNT5a/β-catenin signaling pathways both in tumor tissues and liver tissues of the xenograft models.

• Berberine
• Gastric cancer
• Xenograft models
• Hepatocyte nuclear factor 4α
• WNT5a

Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis, and strategies for clinical management. However, many gastric tumors appear to be resistant to current chemotherapeutic agents. Moreover, a significant number of gastric cancer patients, with a lack of optimal treatment strategies, have reduced survival. In recent years, multiple research data have highlighted the importance of autophagy, an essential catabolic process of cytoplasmic component digestion, in cancer. The role of autophagy as a tumor suppressor or tumor promoter mechanism remains controversial. The multistep nature of the autophagy process offers a wide array of targetable points for designing novel chemotherapeutic strategies. The purpose of this review is to summarize the current knowledge regarding the interplay between gastric cancer development and the autophagy process and decipher the role of autophagy in this kind of cancer. A plethora of different agents that direct or indirect target autophagy may be a novel therapeutic approach for gastric cancer patients.

POU domain, class 2, transcription factor 1 (POU2F1) is involved in the development of gastric cancer (GC). However, the molecular mechanism has not been fully elucidated. Here, we identified a novel lncRNA named TTC3-AS1 that was potentially regulated by POU2F1 and investigated their roles in GC progression. Bioinformatics analysis suggested that high expression of POU2F1 predicted poor prognosis in patients with GC. We further screened out an lncRNA TTC3-AS1 that may be transcriptionally activated by POU2F1 according to the JASPAR database, and POU2F1 and TTC3-AS1 were highly expressed in GC cells and tissues compared with normal controls (NCs). Function analysis revealed that both POU2F1 and TTC3-AS1 played oncogenic roles by promoting cell viability, migration, and invasion in GC. qRT-PCR analysis showed that POU2F1 improved the expression of TTC3-AS1 in GC cells, while TTC3-AS1 knockdown or overexpression had no effect on POU2F1 expression. The results of chromatin immunoprecipitation and DNA-affinity precipitation assays indicated that POU2F1 directly bound to the promoter region of TTC3-AS1 and activated its transcription. TTC3-AS1 knockdown neutralized the protumor effects of POU2F1 overexpression in GC cell lines as well as mouse models of GC, which suggested that TTC3-AS1 mediates the oncogenic function of POU2F1. In summary, POU2F1 promoted GC progression by transcriptionally activating TTC3-AS1; thus, this study provided a new perspective for the mechanism of GC progression.

Gastric cancer (GC) is one of the most common malignancies, and its incidence rates vary widely between men and women. Previous studies have suggested that connexin 43 (Cx43, encoded by gap junction protein alpha 1 (GJA1)) and secretory carrier membrane protein 1 (SCAMP1) are key functional proteins in tumors. Herein, the association between GJA1 and SCAMP1 polymorphisms and GC susceptibility and prognosis was evaluated. A total of three single-nucleotide polymorphisms among 681GC patients and 756 controls were tested using the Agena MassARRAY RS1000 system, including GJA1 rs2071165, SCAMP1 rs4530741, and SCAMP1 rs6874309. The strength of the association with GC risk was assessed by the odds ratios (ORs) and 95% confidence intervals (CIs) generated from the logistic regression model. Kaplan–Meier curve, long-rank tests, and a multivariate Cox proportional hazard model were used for prognosis analysis. The expression of GJA1 was assessed by immunohistochemistry. The GJA1 rs2071165 AA/AG genotype significantly increased the risk of GC in the female Chinese population (OR = 1.55, 95% CI = 1.03–2.32, p=0.034). Furthermore, the risk effect of GJA1 rs2071165 was more evident in the subgroups of female patients with GC, stratified by age, clinical stage, tumor size, and recurrence/metastasis. However, no obvious differences in Cx43 expression in GC tissues were observed between males and females. Furthermore, no significant association between SCAMP1 rs4530741 and rs6874309 polymorphisms and GC risk or prognosis was observed. In conclusion, this study suggests for the first time that the GJA1 rs2071165 polymorphism is associated with increased GC risk in females, revealing a potential new clinical marker for assessing GC risk in females.

Gastric cancer’s bad incidence, prognosis, cellular and molecular heterogeneity amongst others make this disease a major health issue worldwide. Understanding this affliction is a priority for proper patients’ management and for the development of efficient therapeutical strategies. This review gives an overview of major scientific advances, made during the past 5-years, to improve the comprehension of gastric adenocarcinoma. A focus was made on the different actors of gastric carcinogenesis, including, Helicobacter pylori cancer stem cells, tumour microenvironment and microbiota. New and recent potential biomarkers were assessed as well as emerging therapeutical strategies involving cancer stem cells targeting as well as immunotherapy. Finally, recent experimental models to study this highly complex disease were discussed, highlighting the importance of gastric cancer understanding in the hard-fought struggle against cancer relapse, metastasis and bad prognosis.

• EMT
• Helicobacter pylori
• biomarkers
• cancer stem cell
• microbiota
• microenvironment
• stomach cancer

• DY131
• ERRγ
• EZH2
• GSK126
• Gastric tumorigenesis

Influence of folate metabolism has long been studied in cancer and copies evidences have suggested that the key genes involved were correlated with GC risk and prognosis. However, their genetically association and contribution for GC prognosis are still elusive. To evaluate the effect of folate metabolism related genes polymorphisms on the prognosis of gastric cancer (GC), the genotype of seven single nucleotide polymorphisms (SNPs) of three genes were selected and genotyped in a cohort of 664 GC patients, including genes of Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), and Methionine synthase (MTR). Kaplan-Meier Curve, long-rank tests and multivariate Cox proportional hazard model were used for prognosis analysis. The results demonstrated that TT or CT/TT genotypes of SNP rs1532268 in MTRR gene coding region are significantly associated with a poorer overall survival (OS) when compared with CC genotype (HR=2.340, 95% CI: 1.240-4.414, p=0.009; or HR=1.502, 95% CI: 1.083-2.085, p=0.015, respectively). Furthermore, comparing to that of the CC genotype, the detrimental effect of rs1532268 TT genotype was also evident in the special subgroups of GC patients, especially in patients with BMI<24 and H. pylori infection. Moreover, significant association between increased relapse and TT genotype of rs1532268 was also observed in patients who are females, BMI<24 and without chemotherapy. In addition, the joint analysis demonstrated that integration of rs1532268 genotypes and BMI, H. pylori infection status, clinical stage and tumor site may significantly improve the predictive abilities for predicting OS of GC patients. In conclusion, it suggested that the MTRR rs1532268 polymorphism is significantly associated with clinical outcomes of GC patients, especially in those with lower BMI (BMI<24) or positive H. pylori infection status, which warrants further validation. And the polymorphism of MTRR rs1532268 may be a potential prognostic factor for GC patients.

• MTHFR
• MTR
• MTRR
• folate metabolism
• gastric cancer prognosis
• polymorphism

• AIP
• Aryl hydrocarbon receptor interacting protein
• Gastric cancer
• Immunohistochemistry
• Prognosis

• Aged
• Biomarkers, Tumor/metabolism
• Female
• Follow-Up Studies
• Gastrectomy/mortality
• Humans
• Immunohistochemistry
• Intracellular Signaling Peptides and Proteins/metabolism
• Male
• Prognosis
• Retrospective Studies
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Stomach Neoplasms/surgery
• Survival Rate

Abnormal expression of protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) is closely associated with multiple types of cancers. In the present study, we examined the roles of PKMYT1 in gastric cancer (GC) progression.

We examined the expression status of PKMYT1 in GC tissues and cell lines. Meanwhile, short hairpin RNA (shRNA) was used to inhibit the endogenous expression of PKMYT1 in GC cells. Then we analyzed the effect of PKMYT1 on the malignant biological behavior of GC cells by in vitro and in vivo experiments.

The findings showed high PKMYT1 expressions in GC tissues as well as a positive correlation between PKMYT1 expression and prognosis of patients with GC. Additional findings also revealed that PKMYT1 silencing significantly enhanced apoptosis and inhibited GC cell proliferation. In vivo, the silence of PKMYT1 inhibits tumor growth. Further analysis showed that the increase in PKMYT1 expressions led to malignant biological behavior through activation of the MAPK signaling pathway.

Our data suggested that PKMYT1 promotes cell proliferation and apoptosis resistance in GC cells by activating the MAPK signaling pathway, making it a potential therapeutic target for GC.

• MAPK pathway
• PKMYT1
• apoptosis
• gastric cancer
• prognosis
• proliferation

Gastric cancer (GC) is a product of multiple genetic abnormalities, including genetic and epigenetic modifications. This study aimed to integrate various biomolecules, such as miRNAs, mRNA, and DNA methylation, into a genome-wide network and develop a nomogram for predicting the overall survival (OS) of GC.

A total of 329 GC cases, as a training cohort with a random of 150 examples included as a validation cohort, were screened from The Cancer Genome Atlas database. A genome-wide network was constructed based on a combination of univariate Cox regression and least absolute shrinkage and selection operator analyses, and a nomogram was established to predict 1-, 3-, and 5-year OS in the training cohort. The nomogram was then assessed in terms of calibration, discrimination, and clinical usefulness in the validation cohort. Afterward, in order to confirm the superiority of the whole gene network model and further reduce the biomarkers for the improvement of clinical usefulness, we also constructed eight other models according to the different combinations of miRNAs, mRNA, and DNA methylation sites and made corresponding comparisons. Finally, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were also performed to describe the function of this genome-wide network.

A multivariate analysis revealed a novel prognostic factor, a genomics score (GS) comprising seven miRNAs, eight mRNA, and 19 DNA methylation sites. In the validation cohort, comparing to patients with low GS, high-GS patients (HR, 12.886; P < 0.001) were significantly associated with increased all-cause mortality. Furthermore, after stratification of the TNM stage (I, II, III, and IV), there were significant differences revealed in the survival rates between the high-GS and low-GS groups as well (P < 0.001). The 1-, 3-, and 5-year C-index of whole genomics-based nomogram were 0.868, 0.895, and 0.928, respectively. The other models have comparable or relatively poor comprehensive performance, while they had fewer biomarkers. Besides that, DAVID 6.8 further revealed multiple molecules and pathways related to the genome-wide network, such as cytomembranes, cell cycle, and adipocytokine signaling.

We successfully developed a GS based on genome-wide network, which may represent a novel prognostic factor for GC. A combination of GS and TNM staging provides additional precision in stratifying patients with different OS prognoses, constituting a more comprehensive sub-typing system. This could potentially play an important role in future clinical practice.

• DNA methylation
• gastric cancer
• genome-wide network
• mRNA
• miRNA
• nomogram

Background: Transcriptional factors (TFs) are responsible for orchestrating gene transcription during cancer progression. However, their roles in gastric cancer (GC) remain unclear.

Methods: We analyzed the differential expressions of TFs and, using GC cells and tissues, investigated plexin C1 (PLXNC1) RNA levels, as well as PLXNC1's clinical relevance and functional mechanisms. The molecular function of PLXNC1 was evaluated in vitro and in vivo. Kaplan-Meier curves and the log-rank test were used to analyze overall survival (OS) and disease-free survival (DFS).

Results: PLXNC1 was frequently up-regulated in GC and associated with poor prognosis. The expression level of PLXNC1 could serve as an independent biomarker to predict a patient's overall survival. Notably, knockdown of PLXNC1 significantly abolished GC cell proliferation, and migration, and overexpression of PLXNC1 accelerated carcinogenesis in GC. The gene set enrichment analysis (GSEA) indicated that high-expression of PLXNC1 was positively correlated with the activation of epithelial-mesenchymal transition (EMT), TNF-α, and IL-6/STAT3 signaling pathways. PLXNC1 promoted proliferation and migration of GC cells through transcriptional activation of the interleukin 6 signal transducer (IL6ST), which could rescue the malignant behavior of PLXNC1-deficient GC cells.

Conclusions: Our study demonstrated that the PLXNC1 plays an oncogenic role in GC patients. The PLXNC1-IL6ST axis represents a novel potential therapeutic target for GC.

• IL6ST
• PLXNC1
• carcinogenesis
• gastric cancer
• transcriptional factor