Background: As a novel type of noncoding RNAs, covalently closed circular RNAs (circRNAs) are ubiquitously expressed in eukaryotes. Emerging studies have related dysregulation of circRNAs to tumorigenesis. However, the biogenesis, regulation, function and mechanism of circRNAs in gastric cancer (GC) remain largely unclear. Methods: The expression profile of circRNAs in 6 pairs of GC tissues and adjacent non-tumor tissues was analyzed by RNA-sequencing. Quantitative real-time PCR was used to determine the expression level of circCCDC9 in GC tissues and cell lines. Then, functional experiments in vitro and in vivo were employed to explore the effects of circCCDC9 on tumor growth and metastasis in GC. Mechanistically, dual luciferase reporter, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to confirm that circCCDC9 directly sponged miR-6792-3p and alleviated suppression on target CAV1 expression. Results: Evidently down-regulated expression of circCCDC9 was observed in both GC tissues and cell lines. Expression of circCCDC9 was negatively correlated with tumor size, lymph node invasion, advanced clinical stage and overall survival in GC patients. Functionally, overexpression of circCCDC9 significantly inhibited the proliferation, migration and invasion of GC cell lines in vitro and tumor growth and metastasis in vivo, whereas miR-6792-3p mimics counteracted these effects. Mechanistic analysis demonstrated that circCCDC9 acted as a "ceRNA" of miR-6792-3p to relieve the repressive effect of miR-6792-3p on its target CAV1, then suppressed the tumorigenesis of GC. Conclusions: CircCCDC9 functions as a tumor suppressor in inhibiting the progression of GC through miR-6792-3p/ CAV1 axis, which has provided an exploitable biomarker and therapeutic target for patients with GC.

Background Mounting evidences indicate that circular RNAs (circRNAs) play vital roles in the development and progression of various cancers. However, the detail functions and underlying mechanisms of circRNAs in gastric cancer remain largely unknown. Methods The expression profile of metastasis-related circRNAs was screened by RNA-seq analysis. qRT-PCR was used to determine the level and prognostic values of circNHSL1 in gastric cancer tissues. In vitro cell wound healing and transwell (migration and invasion) and in vivo tumorigenesis and metastasis assays were performed to evaluate the functions of circNHSL1. Luciferase reporter, RNA immunoprecipitation (RIP) and rescued assays were employed to confirm the interactions between circNHSL1, miR-1306-3p and SIX1. It’s widely accepted that as a mesenchymal marker, Vimentin promotes invasion and metastasis in various cancers. Luciferase reporter assay was used to determine the regulation of SIX1 on Vimentin. In addition, In situ hybridization (ISH) was performed to detect the level and prognostic values of miR-1306-3p. Results We found that the level of circNHSL1 was significantly up-regulated in gastric cancer, and positively correlated with clinicopathological features and poor prognosis of patients with gastric cancer. Functionally, circNHSL1 promoted cell mobility and invasion, as well as in vivo tumorgenesis and metastasis. Mechanistically, circNHSL1 acted as a miR-1306-3p sponge to relieve the repressive effect of miR-1306-3p on its target SIX1. Moreover, SIX1 enhanced Vimentin expression in the transcriptional level through directly binding to the promoter domain of Vimentin, thereby promoting cell migration and invasion. In addition, miR-1306-3p was down-regulated and negatively correlated with pathological features and poor prognosis in gastric cancer. Conclusions CircNHSL1 promotes gastric cancer progression through miR-1306-3p/SIX1/Vimentin axis, and may serve as a novel diagnostic marker and target for treatment of gastric cancer patients. Electronic supplementary material The online version of this article (10.1186/s12943-019-1054-7) contains supplementary material, which is available to authorized users.

Rationale: As a component of GINS complex, GINS4 is essential for initiating DNA replication and elongation of the cell cycle G1/S phase in eukaryotes and plays a vital role in normal physiological processes. However, the precise functions and regulation mechanisms of GINS4 in human tumors remain elusive.Methods: GINS4 expression was analyzed in gastric cancer tissues by qRT-PCR and western blotting, and its clinical relevance was studied using TMA. The biological functions of GINS4 were detected in vitro and in vivo. cDNA array, co-IP, GST pull-down and GTPase activation assays were performed to investigate the downstream regulation mechanism of GINS4. Upstream regulation mechanism of GINS4 was explored and demonstrated by circRNA sequencing, bioinformatics analysis, luciferase reporter assay and rescue experiments.Results: Strikingly high GINS4 expression was detected in gastric cancer tissues and correlated with poor differentiation, advanced tumor stage, invasion depth and lymph node metastasis. GINS4 promoted cell growth and metastasis in vitro and in vivo, and suppressed cell apoptosis in vitro. Mechanistically, GINS4 activated Rac1/CDC42 through directly binding to Rac1/CDC42, thereby activating their downstream pathways. Furthermore, circMLLT10 acts as a miR-509-3-5p sponge to attenuate its repressive effect on target GINS4. In addition, circMLLT10 promoted cell growth and metastasis and suppressed cell apoptosis, whereas miR-509-3-5p inhibited cell growth and metastasis and promoted cell apoptosis.Conclusion: The findings indicate for the first time that the novel GINS4 axis promotes gastric cancer cell growth and progression by activating Rac1 and CDC42. GINS4 may be a promising biomarker and target for diagnosis and treatment of gastric cancer.

KLF4/PODXL signaling pathway assumes an irreplaceable role in tumorigenesis, invasion and metastasis of human GC and PODXL serves as an independent prognostic indicator for GC patients.