The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42

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.