Circular RNAs (circRNAs) have emerged as essential regulators and biomarkers of various cancers. However, the effects of a novel circRNA termed circGRAMD1B in human gastric cancer (GC) remain unclear. A microarray was used to screen circRNA expression in GC. Quantitative real-time PCR was used to detect the expression of circGRAMD1B. Gain- and loss- of-function experiments were performed to investigate the biological functions of circGRAMD1B in vitro and vivo. Bioinformatics analysis, fluorescence in situ hybridization, dual-luciferase reporter assay, RNA immunoprecipitation, RNA pull-down assay, and rescue experiments were conducted to confirm the underlying mechanisms of competitive endogenous RNAs (ceRNAs). We screened differentially expressed circRNAs and found that circGRAMD1B expression was downregulated in GC tissues and cell lines. Functionally, circGRAMD1B acted as an anti-oncogene and inhibited the proliferation, migration, and invasion abilities of GC cells. Then, we verified that circGRAMD1B served as a sponge that targeted miR-130a-3p in GC cells; circGRAMD1B alleviated GC cell proliferation, migration, and invasion by targeting miR-130a-3p. A mechanistic analysis showed that PTEN and p21 were involved in circGRAMD1B/miR-130a-3p axis-inhibited GC tumorigenesis. Our findings suggest that circGRAMD1B plays an important role in GC progression by regulating miR-130a-3p-PTEN/p21, which may provide a potential biomarker and therapeutic target for GC.

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Circular RNAs (circRNAs) play an essential regulatory role in multiple cancers. However, the role of a large number of circRNAs in gastric cancer (GC) is still unknown. Here, hsa_circ_0139996 (circREPS2), a novel circRNA that was significantly downregulated in GC, was selected for further investigation. circREPS2 was validated and analyzed by DNA sequencing and quantitative real-time PCR. The roles of circREPS2 in GC cells were verified by gain- and loss-of-function experiments. Bioinformatics analysis, luciferase reporter, RNA pull-down, and RNA immunoprecipitation assays were performed to evaluate the functional mechanism of circREPS2 on microRNA-558 (miR-558)/RUNX3/β-catenin axis in GC cells. In the present study, we found that circREPS2 was downregulated in GC tissues and cell lines. Low expression of circREPS2 was associated with a higher tumor-node-metastasis (TNM) stage, poor tumor differentiation, and larger tumor size in GC patients. Functionally, circREPS2 significantly inhibited GC cell proliferation, migration, invasion, and epithelial-mesenchymal transformation (EMT) in vitro and tumorigenesis in vivo . Furthermore, our data demonstrated that circREPS2 acted as a miR-558 sponge and upregulated RUNX3 expression to inactivate β-catenin signaling in GC cells. In conclusion, circREPS2 suppresses the progression of GC via miR-558/RUNX3/β-catenin signaling and is a novel promising biomarker and target for GC treatment.

Esophageal cancer (EC) is a serious malignant tumor, both in terms of mortality and prognosis, and immune-related genes (IRGs) are key contributors to its development. In recent years, immunotherapy for tumors has been widely studied, but a practical prognostic model based on immune-related genes (IRGs) in EC has not been established and reported. This study aimed to develop an immunogenomic risk score for predicting survival outcomes among EC patients. In this study, we downloaded the transcriptome profiling data and matched clinical data of EC patients from The Cancer Genome Atlas (TCGA) database and found 4,094 differentially expressed genes (DEGs) between EC and normal esophageal tissue (p < 0.05 and fold change >2). Then, the intersection of DEGs and the immune genes in the "ImmPort" database resulted in 303 differentially expressed immune-related genes (DEIRGs). Next, through univariate Cox regression analysis of DEIRGs, we obtained 17 immune genes related to prognosis. We detected nine optimal survival-associated IRGs (HSPA6, CACYBP, DKK1, EGF, FGF19, GAST, OSM, ANGPTL3, NR2F2) by using Lasso regression and multivariate Cox regression analyses. Finally, we used those survival-associated IRGs to construct a risk model to predict the prognosis of EC patients. This model could accurately predict overall survival in EC and could be used as a classifier for the evaluation of low-risk and high-risk groups. In conclusion, we identified a practical and robust nine-gene prognostic model based on immune gene dataset. These genes may provide valuable biomarkers and prognostic predictors for EC patients and could be further studied to help understand the mechanism of EC occurrence and development.

Background: Circular RNAs (circRNAs) have been proven to play important roles in tumorigenesis. However, the mechanism by which circRNAs act on gastric cancer (GC) through epithelial-to-mesenchymal transition (EMT) is unclear. In this study, we identified circ-OXCT1 and elucidated its function on EMT in GC. Methods: Tissue circRNA microarray analysis and qRT-PCR were utilized to determine the expression level of circ-OXCT1 in GC. Luciferase reporter assay and FISH were employed to confirm the interaction between circ-OXCT1 and miR-136. CCK-8, cloning formation, transwell, wound healing, nude mice experiment, circ-OXCT1 overexpression and silencing were conducted to elucidate the function of circ-OXCT1 in vivo and in vitro. Western blot and rescue experiment were carried out to evaluate the changes of EMT-related proteins induced by circ-OXCT1 overexpression or silencing. Results: Circ-OXCT1 was downregulated in GC tissues and cell lines. Its expression level was significantly associated with lymph node metastasis, pathologic stage and overall survival rate through clinicopathologic data analysis. Circ-OXCT1 silencing downregulated SMAD4 expression and accordingly regulated expression of E-cadherin, N-cadherin and vimentin through the transforming growth factor-beta (TGF-β)/Smad signaling pathway by a circ-OXCT1/miR-136/SMAD4 axis, resulting in enhancement of EMT and subsequent boost of cell migration, invasion and nude mice lung metastasis. Conclusion: Our data showed that circ-OXCT1 suppresses gastric cancer EMT and metastasis through TGF-β/Smad signaling pathway. The clinicopathologic data analysis revealed that circ-OXCT1 overexpression could be a novel treatment for advanced GC especially with distant metastasis by targeting the circ-OXCT1/miR-136/SMAD4 axis.

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Background: Mounting evidence has displayed critical roles of circular RNAs (circRNAs) in multiple cancers. The underlying mechanisms by which circFGD4 contributed to gastric cancer (GC) are still unclear. Methods: The levels and clinical values of circFGD4 in GC patients were detected and analysed by quantitative real-time PCR. The biological roles of circFGD4 in GC were assessed in vitro and in vivo experiments. Dual-luciferase reporter, fluorescence in situ hybridization, RNA immunoprecipitation, biotin-coupled RNA pull-down, and TOP/Flash and FOP/Flash reporter gene assays were employed to evaluate the effects of circFGD4 on miR-532-3p-mediated adenomatous polyposis coli (APC)/β-catenin signalling in GC cells. Results: circFGD4 expression was down-regulated the most in human GC tissues and cell lines. Low expression of circFGD4 was correlated with poor tumour differentiation, lymphatic metastasis, and poor prognosis of GC patients. circFGD4 suppressed GC cell viability, colony formation, migration, induced epithelial-mesenchymal transition (EMT) and tumorigenesis and metastasis in vivo. Next, we validated that circFGD4 acted as a sponge of miR-532-3p to relieve the tumour-promoting effects of miR-532-3p on its target APC. The mechanistic analysis demonstrated that the circFGD4 suppressed GC cell viability, migration, and EMT by modulating the miR-532-3p/APC axis to inactivate the β-catenin signalling. Conclusion: circFGD4 suppressed GC progression through sponging miR-532-3p and enhancing APC expression to inactivate the β-catenin signalling. Thus circFGD4 provides a novel potential biomarker and valuable therapeutic strategy for GC.

Running heading: ZHX2 predicts poor prognosis in gastric cancer. Abbreviations ZHX2 Zinc-finger and homeoboxes2 GC gastric cancer TIMER Tumor Immune Estimation Resourceti IHC immunohistochemical GSEA Gene set enrichment analysis TCGA The Cancer Genome Atlas qRT-PCR Real-time quantitative PCR CHOL Cholangiocarcinoma ESCA Esophageal carcinoma HNSC Head and Neck squamous cell carcinoma KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LIHC Liver hepatocellular carcinoma SKCM-metastasis Skin Cutaneous Melanoma-metastasis STAD Stomach adenocarcinoma THCA Thyroid carcinoma BLCA Bladder Urothelial Carcinoma KICH Kidney Chromophobe LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma UCEC Uterine Corpus Endometrial Carcinoma OS overall survival FP first progression PPS post progression survival