Polymorphism rs1057147 located in mesothelin gene predicts lymph node metastasis in patients with gastric cancer.

Lymph node metastasis, a crucial factor in the spread of gastric cancer (GC), is strongly associated with a negative prognosis for patients. This study aimed to investigate the association of the mesothelin (MSLN) gene polymorphisms (rs3764247, rs3764246, rs12597489, rs1057147, and rs3765319) with the risk of lymph node metastasis of GC patients in a Chinese Han population. The PCR-LDR genotyping was used to detect the genotypes of MSLN polymorphisms in GC patients with lymph node metastasis (n = 610) or without (n = 356). Our research indicates that certain genetic markers, specifically rs3764247, rs3764246, rs12597489, and rs3765319, do not appear to be linked with an increased risk of lymph node metastasis in GC. However, we did observe that patients with the rs1057147 GA genotype exhibited a higher likelihood of lymph node metastasis in GC when compared to those with the GG genotype (OR = 1.33, 95% CI = 1.01 - 1.76, P = 0.045). Patients with rs1057147 GA + AA genotype were found to have a higher likelihood of lymph node involvement (OR = 1.35, 95% CI = 1.03 - 1.77, P = 0.029) when compared to those with GG genotype in the dominant model. The allelic model revealed that the A allele of rs1057147 exhibited a stronger correlation with lymph node metastasis compared to the G allele (OR = 1.28, 95% CI = 1.02 - 1.60, P = 0.031). In addition, we found that rs1057147 polymorphism revealed a poor prognosis for GC patients with lymph node metastasis. Further stratified analysis revealed that the prognostic effect of rs1057147 was more pronounced in patients with GC who had lymph node metastasis and had a tumor size of 4 cm or greater, as well as more than 2 lymph node metastases. Bioinformatics studies showed that the binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147. Our study confirmed the important role of MSLN rs1057147 polymorphism locus in GC lymph node metastases and suggested a potential prognostic factor during GC progression. KEY POINTS: • Rs1057147 GA genotype had an increased risk of lymph node metastasis in gastric cancer. • The A allele of rs1057147 had a stronger association with lymph node metastasis than the G allele. • The binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147.

Prognostic Value of Tumor Size in Gastric Cancer: A Retrospective Cohort Study Based on SEER Database.

Background. Although tumor size is regarded as the "T" stage of the tumor-node-metastasis (TNM) staging system for many solid tumors, its prognostic impact in gastric cancer remains uncertain and conflicting. Methods. We enrolled 6960 eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database. The X-tile program was used to select the best cut-off value of tumor size. Then, the Kaplan-Meier method and the Cox proportional hazards model were applied to examine the efficacy of tumor size on prognostic prediction for overall survival (OS) and gastric cancer-specific survival (GCSS). The presence of nonlinear association was determined by the restricted cubic spline (RCS) model. Results. Tumor size was divided into 3 groups: small size (≤2.5 cm), medium size (2.6-5.2 cm), and large size (≥5.3 cm). After adjusting by covariates such as depth of tumor infiltration, the large and medium groups showed a worse prognosis than the small group; however, no survival difference in OS was suggested between the medium and large groups. Similarly, although there was a nonlinear relationship between tumor size and survival, increasing tumor size did not show an independent negative effect on prognosis in the RCS analysis. However, the stratified analyses proposed this 3-way cut of tumor size in prognostic prediction for patients with both inadequate lymphadenectomy and negative nodal metastasis. Conclusions. Tumor size as a prognostic predictor may not have good clinical applicability in gastric cancer. Otherwise, it was recommended for patients with both insufficient examinations of lymph nodes and stage N0 disease.

A novel risk model construction and immune landscape analysis of gastric cancer based on cuproptosis-related long noncoding RNAs.

Recent studies have identified cuproptosis, a new mechanism of regulating cell death. Accumulating evidence suggests that copper homeostasis is associated with tumorigenesis and tumor progression, however, the clinical significance of cuproptosis in gastric cancer (GC) is unclear. In this study, we obtained 26 prognostic cuproptosis-related lncRNAs (CRLs) based on 19 cuproptosis-related genes (CRGs) via Pearson correlation analysis, differential expression analysis, and univariate Cox analysis. A risk model based on 10 CRLs was established with the least absolute shrinkage and selection operator (LASSO) Cox regression analysis and multivariate Cox proportional hazards model to predict the prognosis and immune landscape of GC patients from The Cancer Genome Atlas (TCGA). The risk model has excellent accuracy and efficiency in predicting prognosis of GC patients (Area Under Curve (AUC) = 0.742, 0.803, 0.806 at 1,3,5 years, respectively, P < 0.05). In addition, we found that the risk score was negatively correlated with the infiltration of natural killer (NK) cells and helper T cells, while positively correlated with the infiltration of monocytes, macrophages, mast cells, and neutrophils. Moreover, we evaluated the difference in drug sensitivity of patients with different risk patterns. Furthermore, low-risk patients showed higher tumor mutation burden (TMB) and better immunotherapy response than high-risk patients. In the end, we confirmed the oncogenic role of AL121748.1 which exhibited the highest Hazard Ratio (HR) value among 10 CRLs in GC via cellular functional experiments. In conclusion, our risk model shows a significant role in tumor immunity and could be applied to predict the prognosis of GC patients.

Correlation of MIF-AS1 polymorphisms with the risk and prognosis of gastric cancer.

BACKGROUND: The most studied genetic polymorphisms associated with gastric cancer (GC) risk are located in protein-coding genes. However, the localization of these in long non-coding RNAs (lncRNAs) has not been fully studied. We aim to investigate the associations of Long non-coding RNA macrophage migration inhibitory factor antisense RNA1(Lnc-MIF-AS1) five polymorphisms (rs755622, rs17004044, rs2070767, rs1007889, rs2000468) with the risk and prognosis of GC. METHODS: A total of 844 GC patients and 871 controls were included in the study. Genotyping was carried out using polymerase chain reaction-ligase detection reaction (PCR-LDR) technology. Odds ratios (ORs) and 95% confidence intervals (CIs) generated from unconditional logistic regression, were applied to quantify the effects of MIF-AS1 gene SNPs on GC risk. Log-rank test and Cox regression analysis were fitted to estimate hazard ratios (HRs) to quantify the effects of MIF-AS1 gene SNPs on GC prognosis. RESULTS: Significant associations were identified between MIF-AS1 rs17004044 variants and GC group in the codominant, dominant and additive models (OR = 2.843, P = 0.010; OR = 1.370, P = 0.004; and OR = 1.386; P = 0.001). In addition, association between rs17004044 variants and survival of GC was extremely observed (TC HR = 2.02 (1.21-3.37) P = 0.007, CC HR = 5.61 (2.12-14.83), P = 0.001). CONCLUSION: MIF-AS1 polymorphism rs17004044 contributes to increased predisposition and prognosis to GC.

Polymorphisms of an oncogenic gene, mesothelin, predict the risk and prognosis of gastric cancer in a Chinese Han population.

Mesothelin (MSLN) is a cell surface protein associated with tumor invasion and metastasis. This study aims to explore the biological function of MSLN in gastric cancer and to evaluate the association of MSLN polymorphism (rs3764247, rs3764246, rs12597489, rs1057147, rs3765319) with the risk and prognosis of gastric cancer. Small interfering RNA (siRNA) transfection and MSLN overexpression were performed in human gastric cancer cell lines, respectively. The proliferation of tumor cells was evaluated by Cell counting kit 8(CCK-8) and colony formation assay. Wound healing assay and transwell assay were used to elucidate gastric cancer cell migration and invasion rates. We conducted a case-control study involving 860 patients with gastric cancer and 870 controls. All mutation sites were genotyped by PCR-LDR sequencing. First, our study revealed the cancer-promoting role of MSLN in gastric cancer. Second, we also demonstrated that rs3764247 and rs3764246 were associated with a reduced risk of gastric cancer (OR = 0.83, p = 0.010; OR = 0.84, p = 0.011; respectively). The clinicopathological analysis further showed that rs3764247 was closely related to T stage, vascular infiltration, and HER2 expression. In addition, in the survival analysis of 392 patients with gastric cancer, patients with rs3764247 CC genotype had poorer survival than patients with AA + AC genotype after adjusting for age, sex, TNM stage, and Lauren classification (HR = 2.07, p = 0.029). Our findings indicated that MSLN could be an oncogene whose polymorphisms were closely related to the risk and prognosis of gastric cancer.

Long noncoding RNA FAM225A promotes the malignant progression of gastric cancer through the miR-326/PADI2 axis.

Gastric cancer (GC) is a global health problem and further studies of its molecular mechanisms are needed to identify effective therapeutic targets. Although some long noncoding RNAs (lncRNAs) have been found to be involved in the progression of GC, the molecular mechanisms of many GC-related lncRNAs remain unclear. In this study, a series of in vivo and in vitro assays were performed to study the relationship between FAM225A and GC, which showed that FAM225A levels were correlated with poor prognosis in GC. Higher FAM225A expression tended to be correlated with a more profound lymphatic metastasis rate, larger tumor size, and more advanced tumor stage. FAM225A also promoted gastric cell proliferation, invasion, and migration. Further mechanistic investigation showed that FAM225A acted as a miR-326 sponge to upregulate its direct target PADI2 in GC. Overall, our findings indicated that FAM225A promoted GC development and progression via a competitive endogenous RNA network of FAM225A/miR-326/PADI2 in GC, providing insight into possible therapeutic targets and prognosis of GC.

Genetic polymorphisms of Cathepsin B are associated with gastric cancer risk and prognosis in a Chinese population.

BACKGROUND: Genetic polymorphisms are believed to represent a key aspect of predisposition to gastric cancer (GC). Therefore, considering the important role of Cathepsin B (CTSB) in promoting cancer onset and development, it could be very worthful to explore the function of CTSB-related genetic polymorphisms in GC. OBJECTIVE: In this study, we investigated the correlation of CTSB-related polymorphisms (rs9009A>T, rs6731T>C, rs1293303G>C, rs1874547C>T, rs3779659C>T, rs17814426C>T and rs148669985C>T) with GC risk and prognosis in a case-control study of 994 cases and 1000 controls. METHODS: All tag single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-ligase detection reaction (PCR-LDR) sequencing technology. RESULTS: The results indicated rs9009, rs6731 and rs17814426 correlated with decreased risks of GC (HR = 0.97, p< 0.001; HR = 0.86, P= 0.019; HR = 0.85, P= 0.017; respectively). Stratification analysis further showed rs17814426 variant genotypes correlated with earlier T stage (p= 0.044). In addition, GC patients carrying the C allele of rs6371 had better overall prognosis (HR = 0.62, 95%CI = 0.44-0.88). CONCLUSION: Our results firstly suggested the importance of CTSB-related polymorphisms on GC which could predict GC risk and prognosis.

MicroRNA-653-5p Promotes Gastric Cancer Proliferation and Metastasis by Targeting the SOCS6-STAT3 Pathway.

MicroRNAs (miRNAs) are emerging as significant regulators of the tumorigenesis of gastric cancer (GC), and may be effective biomarkers for diagnosis, prognosis, and therapeutic targeting for GC. In this study, miR-653-5p was found to be significantly upregulated in GC tissues, serum, and cell lines and was strongly associated with poor prognosis in patients with GC. Furthermore, miR-653-5p promoted GC cell proliferation and metastasis in vivo and in vitro. Suppressor of cytokine signaling 6 (SOCS6) was directly targeted by miR-653-5p, and SOCS6 attenuated miR-653-5p-mediated GC cell growth, migration, and invasion. In addition, SOCS6-mediated inactivation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was also reversed by the administration of miR-653-5p. The findings from this study support a novel regulatory axis between miR-653-5p, SOCS6, and JAK2/STAT3 that may be a target for diagnosis and therapeutic intervention for GC.

Correlations of SNHG5 genetic polymorphisms with susceptibility and prognosis to gastric cancer in a Chinese population.

The most studied genetic polymorphisms associated with gastric cancer (GC) risk are located in protein-coding genes. However, these sited in long noncoding RNA (lncRNA) are not adequately explored yet. Here, we designed a case-control study of 848 cases and 880 controls to investigate the associations of polymorphisms (rs61396151, rs1059307, rs11961028, rs9351065) in lncRNA SNHG5 with the risk and prognosis of GC. The results indicate rs61396151 associated with decreased risk of GC (OR = 0.78, 95% CI = 0.62-0.96), but there were no correlations observed with the clinicopathological features of GC (P > 0.05). However, the CA genotype of rs61396151 was correlated with poor overall survival rate in a multivariate cox regression model (HR = 1.91, P = 0.040), but it was reversed with adjustment for age, gender and TNM stage (HR = 1.35, P = 0.213). Collectively, our results highlight the importance of SNHG5-related polymorphisms to GC susceptibility and prognosis.

Long non-coding RNA CCDC144NL-AS1 sponges miR-143-3p and regulates MAP3K7 by acting as a competing endogenous RNA in gastric cancer.

Gastric cancer (GC) has been one of the most leading cause of cancer-death worldwide. Long non-coding RNAs (lncRNAs) have been found to be related with the carcinogenesis and the development of various cancers, including GC. However, there are still many GC-related lncRNAs functional roles and molecular mechanisms that have not yet been clearly studied. Herein, we report lncRNA CCDC144NL-AS1, which has not been explored in GC, and it is markedly upregulated in GC tissues, which may serve as an independent predictor of poor prognosis. We found that CCDC144NL-AS1 expression was significantly positively associated with a larger tumor size and more pronounced lymph node metastasis. Through a series of in vivo and in vitro functional experiments, we observed that CCDC144NL-AS1 could facilitate cell proliferation, invasion and migration and inhibit cell apoptosis in GC. Further mechanism investigation revealed that CCDC144NL-AS1 acted as a competing endogenous RNA (ceRNA) for sponging miR-143-3p and upregulated the expression of its direct endogenous target MAP3K7 in GC. Taken together, our results elucidate the oncogenic roles of CCDC144NL-AS1/miR-143-3p/MAP3K7 axis in GC progression, providing inspiration for further understanding of the mechanism of GC and making CCDC144NL-AS1 as a potential novel diagnostic and therapeutic target for GC.

Long noncoding RNA TRPM2-AS acts as a microRNA sponge of miR-612 to promote gastric cancer progression and radioresistance.

Long noncoding RNAs (lncRNAs) are emerging as important regulators of tumorigenesis and are frequently dysregulated in cancers. Here, we identify a critical lncRNA TRPM2-AS which is aberrantly expressed in gastric cancer (GC) tissues by screening The Cancer Genome Atlas Program(TCGA) database of GC cohort, and its upregulation is clinically associated with advanced pathologic stages and poor prognosis in GC patients. Silencing TRPM2-AS inhibits the proliferation, metastasis and radioresistance of GC cell whereas ectopic expression of TRPM2-AS significantly improves the progression of GC cell in multiple experiments. Mechanistically, TRPM2-AS serves as a microRNA sponge or a competitive endogenous RNA (ceRNA) for tumor suppressive microRNA miR-612 and consequently modulates the derepression of IGF2BP1 and FOXM1. Moreover, induced upregulation of IGF2BP1 subsequently increases the expression of c-Myc and promotes GC cell progression. Meanwhile, TRPM2-AS promotes the radioreistance of GC cell through enhancing the expression of FOXM1 as well. Thus, our findings support a new regulatory axis between TRPM2-AS, miR-612, IGF2BP1, or FOXM1 which serve as crucial effectors in GC tumorigenesis and malignant development, suggesting a promising therapeutic and diagnostic direction for GC.