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Gastric cancer (GC) is a common form of cancer and the leading cause of cancer-related deaths worldwide. Chemotherapy is the primary treatment for patients with unresectable or partially resectable GC. However, its adverse effects and chemoresistance greatly restrict its applicability and efficacy. Although HER2-targeted therapy and immunotherapy have been successfully used for GC treatment, their beneficial population is limited. To expand the range of cancer treatments, drug repurposing has emerged as a promising strategy. In this study, we evaluated the potential of Metformin, an oral anti-hyperglycemic agent, to suppress GC progression both in vivo and in vitro. Functional investigations showed that Metformin significantly inhibits GC proliferation and migration. Furthermore, we discovered that Metformin bound and disrupted STAT1 phosphorylation, inhibiting PRMT1 expression and consequently GC progression. In conclusion, our study not only provides further evidence for the anti-GC role of Metformin but also identifies the direct target mediating the tumor-inhibitory effects of Metformin in GC. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most prevalent digestive malignancies. A great number of patients at first visit or post curative resections are diagnosed with widespread metastasis within the peritoneal cavity. Overwhelming evidence has demonstrated that exosomes, a variety of biologically functional extracellular vesicles comprising active factors, mediate the progression and metastasis of GC. Although the regulatory mechanisms of exosomes remain fairly elusive, they are responsible for intercellular communication between tumor cells and normal stroma, cancer-related fibroblasts, immune cells within the primary tumor and metastatic niche. In this review, we provide new insight into the molecular signatures of GC-associated exosomes in reprogramming the tumor microenvironment and the subsequent promotion of peritoneal metastasis—including infiltration of the gastric wall, implantation of tumor cells onto the pre-metastatic peritoneum, and remodeling of the pre-metastatic niche. Based on this review, we hope to draw a more general conclusion for the functions of exosomes in the progression and peritoneal metastasis of GC and highlight the future perspective on strategies targeting exosomes in prognostic biomarkers and therapy for peritoneal metastasis. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is the fifth most frequently diagnosed malignancy, and the third leading cause of tumor-related mortalities worldwide. Due to a high heterogeneity in GC, its treatment and prognosis are challenging, necessitating urgent identification of novel prognostic predictors for GC patients. Methods: We downloaded RNA sequence data, from the Cancer Genome Atlas and microarray data from Gene Expression Omnibus database, then identified common differentially-expressed genes (DEGs) between GC and normal gastric tissues across four datasets. We then used a combination of protein-protein interaction (PPI) network and weighted gene co-expression network analysis (WGCNA) to identify key genes with prognostic value in GC. Thereafter, we used quantitative real time polymerase chain reaction (qRT-PCR) to validate expression of the identified key genes in the Zhejiang University (ZJU) cohort. Finally, we evaluated the relationships between gene expression and immune factors, including immune cells and biomarkers of immunotherapy. Results: Among 426 common DEGs screened, 333 and 93 were upregulated and downregulated, respectively. PPI network and WGCNA successfully identified the top 30 hub genes, among which PTPRC, TYROBP, CCR1, CYBB, LCP2 , and C1QB were common. Furthermore, TYROBP and C1QB were negatively associated with prognosis of GC patients, implying that they were key GC predictors. Interestingly, TYROBP and C1QB were positively correlated with predictive biomarkers for GC immunotherapy, including PD-L1 expression, CD8+ T cells infiltration, and EBV status. Conclusions: TYROBP and C1QB were identified as two novel key genes with prognostic value in GC by network analysis. [ABSTRACT FROM AUTHOR]

The present study aimed to identify genes associated with gastric cancer survival and improve risk stratification for patients with gastric cancer. Transcriptomic and clinicopathological data from 443 gastric cancer samples were retrieved from The Cancer Genome Atlas database. The DESeq R package was applied to screen for differentially expressed genes between Tumor-Node-Metastasis (TNM) stage (I vs. IV) and histological grade (G3 vs. G1 and G2). A total of seven genes were common to both comparisons; spondin 1 (SPON1); thrombospondin 4 (THBS4); Sushi, Von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1); prickle planar cell polarity protein 1 (PRICKLE1); ATP binding cassette subfamily A member 8 (ABCA8); Slit guidance ligand 2 (SLIT2); and EGF containing fibulin extracellular matrix protein 1 (EFEMP1), were selected as candidate survival-associated genes for further analysis. The prognostic value of these genes was assessed according to a literature review and Kaplan-Meier survival analysis. In addition, a multivariate Cox regression analysis revealed PRICKLE1 expression to be an independent prognostic factor for patients with gastric cancer. Furthermore, a predictive nomogram was generated using PRICKLE1 expression, patient age and TNM stage to assess overall survival (OS) rate at 1, 3 and 5 years, with an internal concordance index of 0.65. External validation was conducted in an independent cohort of 59 patients with gastric cancer, and high consistency between the predicted and observed results for OS was exhibited. Overall, the current findings suggest that PRICKLE1 expression may serve as an independent prognostic factor that can be integrated with age and TNM stage in a nomogram able to predict OS rate in patients with gastric cancer. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a frequently occurring malignancy with high mortality rates. However, the underlying mechanism of GC progression is not very clear. The aim of this study is to reveal the inherent molecular mechanism and develop potential therapeutic targets for advanced GC. The microfibril-associated glycoprotein 1 (MAGP1), identified as a potential oncogene, was found upregulated in GC tissues and high MAGP1 expression was associated with aggressive clinicopathological features. Furthermore, the multivariate Cox regression analysis showed that high MAGP1 expression was an independent predictor of poor prognosis (HR = 2.37, 1.07–5.24; P = 0.033). Mechanistically, MAGP1 promoted the migration and invasiveness of GC cells. In addition, the genes co-expressed with MAGP1 were primarily enriched in focal adhesion and PI3K-Akt pathways. MAGP1 overexpression enhanced the phosphorylation of FAK, AKT, and mTOR, whereas its knockdown also inactivated these factors. Furthermore, the AKT inhibitor suppressed the phosphorylation of AKT, FAK, and mTOR in recMAGP1-treated AGS cells, as well as their migration and invasion capacities. Finally, correlation analysis indicated that MAGP1 is involved in AKT signaling in GC, and is clinically relevant. Taken together, MAGP1 is a promising prognostic marker and potential therapeutic target for advanced GC. [ABSTRACT FROM AUTHOR]

Abstract Background The miR-129-5p has been reported to be aberrant expression and exert vital roles in tumor progression of various malignancies. However, the effects on EMT in gastric cancer and its precise molecular mechanism in gastric cancer remain unclear. Methods and materials RT-qPCR was performed to evaluate the expression level of miR-129-5p and HMGB1 in cell lines. Cell proliferation was detected via CCK-8. The epithelial mesenchymal transition (EMT) related proteins and the expression of HMGB1 were detected by western blot analysis. Luciferase assays were used to validate binding seeds between miR-129-5p and HMGB1. Results miR-129-5p was downregulated in gastric cancer cells compared with GES-1. At the same time EMT was promoted in gastric cancer cells compared to GES-1. Overexpression of miR-129-5p inhibited EMT and proliferation. MiR-129-5p negatively and directly targeted HMGB1. HMGB1 was upregulated in gastric cancer cells and HMGB1 knocked-down inhibited EMT and cell proliferation. Conclusion Taken together, upregulation of miR-129-5p associated with gastric cancer proliferation and EMT, and serves as a potential diagnostic and therapeutic target via miR-129-5p/HMGB1 pathway in gastric cancer. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a leading cause of worldwide cancer-related death. Being a highly heterogeneous disease, the current treatment of GC has been suboptimal due to the lack of subtype-dependent therapies. Peritoneal dissemination (PD) is a common pattern of GC metastasis associated with poor prognosis. Therefore, it is urgently necessary to identify patients at high risk of PD. PD is found to be associated with Lauren diffuse type GC. Molecular profiling of GC, especially diffuse type GC, has been utilized to identify molecular alterations and has given rise to various molecular classifications, shedding light on the underlying mechanism of PD and enabling identification of patients at higher PD risk. In addition, a series of diagnositc and prognostic biomarkers of PD from serum, peritoneal lavages and primary GCs have been reported. This comprehensive review summarizes findings on the multi-omic characteristics of diffuse type GC, the clinical significance of updating molecular classifications of GC in association with PD risk and research advances in PD-associated biomarkers. [ABSTRACT FROM AUTHOR]

Gastric cancer stem cells (GCSCs) are strongly associated with the refractory characteristics of gastric cancer, including drug resistance, recurrence, and metastasis. The prognosis for advanced gastric cancer patients treated with multimodal therapy after surgery remains discouraging. GCSCs hold promise as therapeutic targets for GC patients. We obtained 26 sets of stem cell-related genes from the StemChecker database. The Consensus clustering algorithm was employed to discern three distinct stemness subtypes. Prognostic outcomes, components of the tumor microenvironment (TME), and responses to therapies were compared among these subtypes. Following this, a stemness-risk model was formulated using weighted gene correlation network analysis (WGCNA), alongside Cox regression and random survival forest analyses. The C2 subtype predominantly showed enrichment in negative prognostic CSC gene sets and demonstrated an immunosuppressive TME. This specific subtype exhibited minimal responsiveness to immunotherapies and demonstrated reduced sensitivity to drugs. Four pivotal genes were integrated into the construction of the stemness model. Gastric cancer patients with higher stemness-risk scores demonstrated poorer prognoses, a greater presence of immunosuppressive components in TME, and lower rates of treatment response. Subset analysis indicated that only the low-stemness risk subtype derives benefit from 5-fluorouracil-based adjuvant chemotherapy. The model's effectiveness in immunotherapeutic prediction was further validated in the PRJEB25780 cohort. Our study categorized gastric cancer patients into three stemness subtypes, each demonstrating distinct prognoses, components of TME infiltration, and varying sensitivity or resistance to standard chemotherapy or targeted therapy. We propose that the stemness risk model may help the development of well-grounded treatment recommendations and prognostic assessments. • The expression levels of M2 polarization regulators were significantly elevated in the high-risk stemness group. • In the high stemness-risk group, there was no significant difference in RFS rates between patients with or without adjuvant chemotherapy. • we conducted (2^10-1) iterations to select gene combinations based on the lowest log-rank p-value. • Transfection with FERMT2-siRNA led to a decrease in the expression levels of various stemness-related markers. [ABSTRACT FROM AUTHOR]