Demethylase FTO Enhances The PI3K/Akt Signaling To Promote Gastric Cancer Malignancy

Objective:Enhanced expression of fat mass and obesity-associated protein(FTO)has been reported in gastric cancer(GC).Bioinformatical studies indicate that FTO expression is correlated with the patients’ overall survival(OS).How FTO exerts its promotion effects on GC development and affects OS remains largely unknown.In this study,the prognostic relevance of FTO expression in human GC tissues and the molecular mechanisms underlying FTO’s promotion roles were investigated.Methods:FTO expression was analyzed by immunohistochemistry(IHC)in a human GC tissue chip,and the association of its expression status with prognosis was then evaluated.Using FTO knockdown and overexpression,FTO-exerted promotion effects on malignant phenotypes in GC cells was investigated in vitro and in a mouse xenograft model.High-throughput transcriptome sequencing was conducted to identify differentially expressed genes and associated signaling pathways.Results:Kaplan-Meier survival curve analysis revealed that the patients with high FTO levels had shorter OS compared to those with low FTO expression(p<0.0001).Univariate and multivariate COX regression analyses showed that the patients’ OS was affected by FTO status(p<0.0001,p<0.0001,respectively).FTO knockdown in HGC27 cells by sh RNAs reduced cell proliferation,colony formation,migration and invasion,while FTO overexpression in AGS cells had reverse effects.FTO knockdown in HGC27 cells also suppressed the tumor growth in a mouse xenograft model.High-throughput transcriptome sequencing indicated that FTO enhanced the PI3K/Akt signaling,which was confirmed in vitro.Conclusions:In summary,our research revealed that FTO is a potent prognostic biomarker of GC.FTO enhances the PI3K/Akt signaling and thus,promotes GC development.