Ferroptosis is a regulated cell death nexus linking metabolism, redox biology and diseases including cancer. The aim of the present study was to identify a ferroptosis‐related gene prognostic signature for stomach adenocarcinoma (STAD) by systematic analysis of transcriptional profiles from The Cancer Genome Atlas (TCGA), GEO and a clinical cohort from our centre. We developed a predictive model based on three ferroptosis‐related genes (CHAC1, NOX4 and HIF1A), gene expression data and corresponding clinical outcomes were obtained from the TCGA database, and the reliability of this model was verified with GSE15459 and 51 queues in our centre. ROC curve showed better predictive ability using the risk score. Immune cell enrichment analysis demonstrated that the types of immune cells and their expression levels in the high‐risk group were significantly different from those in the low‐risk group. The experimental results confirmed that NOX4 was upregulated and CHAC1 was downregulated in the STAD tissues compared with the normal stomach mucosal tissues (p < 0.05). In sum, the ferroptosis‐related gene signature can accurately predict the outcomes of patients with STAD, providing valuable insights for personalized treatment. As the signature also has relevance to the immune characteristics, it may help improve the efficacy of personalized immunotherapy.

Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata, is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.

Globally, the incidence and mortality rates of gastric cancer are high, and its poor prognosis is closely related to tumor recurrence and metastasis. Therefore, the molecular mechanisms associated with the migration and invasion of gastric cancer cells are important for gastric cancer treatment. Previously, TSPAN9 has been reported to inhibit gastric cancer cell migration; however, the underlying molecular mechanism remains unclear. Human gastric adenocarcinoma cell lines, SGC7901 and AGS, were cultured in vitro. TSPAN9 expression was determined by RT-PCR, western blot analysis, and immunohistochemistry in gastric cancer and tumor-adjacent tissues. Following the over-expression and knockdown of TSPAN9, wound healing and cell invasion assays were performed and EMT-related protein expression was evaluated to analyze the invasion and migration of gastric cancer cells. TSPAN9 expression and the invasion and metastasis of gastric cancer cells were observed by the functional assays following EMILIN1 over-expression. Inhibiting TSPAN9 expression significantly promoted the migration and invasion of gastric cancer cells. In addition, immunofluorescence co-localization and co-immunoprecipitation analysis revealed closely related expression of EMILIN1 and TSPAN9. Moreover, EMILIN1 can synergistically boost the tumor suppressive effect of TSPAN9, which may be produced by promoting TSPAN9 expression. We have demonstrated that EMILIN1 induces anti-tumor effects by up-regulating TSPAN9 expression in gastric cancer. Hence, membrane proteins TSPAN9 and EMILIN1 may represent novel therapeutic targets for the treatment of gastric cancer.

Advanced gastric cancer has a poor prognosis because of advanced gastric cancer is prone to metastasis. It is urgent for us to find an indicator to predict the prognosis of gastric cancer in a timely fashion. Research has revealed that inflammation has an important role in predicting survival in some cancers. The purpose of this study was to evaluate the significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) on the prognosis of metastatic gastric cancer (GC). This was a retrospective review of 110 patients were at presentation diagnosed with stage IV metastatic GC and all patients received palliative chemotherapy between January 2012 and January 2016 at the Affiliated Hospital of Qingdao University. Pretreatment NLR and PLR, as well as clinicopathological characteristics were collected. Patients were divided into high and low groups according to the cutoff values for NLR and PLR. The Kaplan–Meier method was applied to estimate the overall survival (OS) and the Cox proportional hazards model to evaluate the related risk factors for OS. All tests were 2-tailed and a P < .05 was considered to indicate a statistically significant difference. One hundred ten patients were enrolled. Eighty-four patients were men, 24 patients were women, 61 patients were ≥65 years of age, and 49 patients were <65 years of age. The Eastern Cooperative Oncology Group (ECOG) score of most patients (n = 107) ranged from 0 to 1. Ten patients were human epidermal growth factor receptor 2 (HER2)-positive. Seventy-one patients presented with an elevated carcinoembryonic antigen (CEA) level and 49 patients had an elevated Carcinoembryonic 199 (CA-199) level. Fifty-two patients received first-line chemotherapy only. Nineteen patients received third-line or greater chemotherapy. One hundred patients chose dual drug chemotherapy. The median duration of follow-up was 11.6 months. Based on the receiver operating characteristic (ROC) curve, the optimal cut-off value for NLR and PLR was 2.48 and 143.39. Patients with high NLR and high PLR had poor overall survival compared with those who had low NLR and low PLR (P < .001 and P = .013, respectively). In univariate analysis, old age (P = .013), liver metastasis (P = .001), >1 metastatic sites (P = .028), higher NLR (P = .000), and higher PLR (P = .014) were identified as poor prognostic factors associated with OS. Our multivariate analysis had indicated that high NLR (hazard ratio [HR]: 1.617, 95% CI: 1.032–2.525, P = .036) and peritoneal metastasis (HR: 1.547, 95% CI:1.009–2.454, P = .045) was independent prognostic factors for overall survival; however, the PLR was not shown to be an independent prognostic factor. Our study suggested that the pretreatment NLR can be used as significant prognosis biomarker in metastatic gastric cancer patients receiving palliative chemotherapy.

Background: Liver hepatocellular carcinoma (HCC) is a prevalent cancer that lacks a sufficiently efficient approach to guide immunotherapy. Additionally, cuproptosis is a recently identified regulated cell death program that is triggered by copper ionophores. However, its possible significance in tumor immune cell infiltration is still unclear.Methods: Cuproptosis subtypes in HCC were identified using unsupervised consensus cluster analysis based on 10 cuproptosis regulators expressions, and a cuproptosis-related risk signature was generated using univariate and LASSO Cox regression and validated using the ICGC data. Moreover, the relationship between signature and tumor immune microenvironment (TME) was studied through tumor immunotherapy responsiveness, immune cell infiltration, and tumor stem cell analysis. Finally, clinical specimens were analyzed using immunohistochemistry to verify the expression of the three genes in the signature.Results: Two subtypes of cuproptosis regulation were observed in HCC, with different immune cell infiltration features. Genes expressed differentially between the two cuproptosis clusters in the TCGA were determined and used to construct a risk signature that was validated using the ICGC cohort. Greater immune and stromal cell infiltration were observed in the high-risk group and were associated with unfavorable prognosis. Elevated risk scores were linked with higher RNA stemness scores (RNAss) and tumor mutational burden (TMB), together with a greater likelihood of benefitting from immunotherapy.Conclusion: It was found that cuproptosis regulatory patterns may play important roles in the heterogeneity of immune cell infiltration. The risk signature associated with cuproptosis can assess each patient’s risk score, leading to more individualized and effective immunotherapy.

Tetraspanins are a heterogeneous group of 4-transmembrane proteins that recruit other cell surface receptors and signaling proteins into tetraspanin-enriched microdomains (TEMs). TEMs of various types are involved in the regulation of cell growth, migration and invasion of several tumor cell types, both as suppressors or promotors. Tetraspanin 9 (Tspan9, NET-5, PP1057), a member of the transmembrane 4 superfamily (TM4SF) of tetraspanins, reportedly regulates platelet function in concert with other platelet tetraspanins and their associated proteins. Our previous study demonstrated that Tspan9 is also expressed in gastric cancer (GC), but the role of Tspan9 in GC has not been well characterized. In this study, we investigated the influence of Tspan9 on proliferation, migration and invasion of human gastric cancer SGC7901 cells using CCK-8 assay, cell cycle analysis, wound-healing assay and Transwell assay. Western blot analysis and ELISA assay were also performed to identify the potential mechanisms involved. The proliferation, migration and invasion of human gastric cancer SGC7901 cells were significantly inhibited by overexpression of Tspan9. In addition, Tspan9 downregulated the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the secretion levels of proteins related to tumor metastasis, such as matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (uPA). Our study indicated that Tspan9 inhibited SGC7901 cell proliferation, migration and invasion through the ERK1/2 pathway.