E2F2 Inhibition Induces Autophagy to Impair Metastasis via the PI3K/Akt/mTOR Pathway in Gastric Cancer

Background: E2F2 is a member of the E2F transcription factor family and has important but not fully understood biological functions in cancers. The pro- and antitumor functions of E2F2 in some cancer types are controversial. However, the biological role of E2F2 in gastric cancer (GC) remains unclear.MethodsE2F2 expression from multiple gene expression databases was analyzed. Kaplan-Meier plots and Cox regression were used to analyze the prognostic value of E2F2 expression. The correlation between E2F2 and tumor immune infiltration was investigated using the Tumor Immune Estimation Resource (TIMER) database. The functions and pathways of E2F2 and its 50 most highly correlated genes in terms of expression pattern were analyzed using Database Annotation, Visualization, and Integrated Discovery (DAVID) software. We used immunohistochemistry, real-time quantitative polymerase chain reaction, and western blotting to detect the expression level of E2F2 in GC. We further investigated the effects of E2F2 on phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling, autophagy, and the migration and invasion of GC cells by the wound healing assay, Transwell assay, western blotting, and transmission electron microscopy.ResultsE2F2 was highly expressed in both GC tissues and cells compared with normal gastric tissues/cells in public datasets and our validation experiments. High E2F2 expression was associated with poor overall survival (OS). In addition, the expression of E2F2 in GC had a strong correlation with a variety of immune markers. E2F2 overexpression promoted the migration and invasion of GC cells in vitro through the inhibition of PI3K/Akt/mTOR-mediated autophagy. In contrast, inhibition of E2F2 inhibited the migration and invasion of GC cells in vitro by activating PI3K/Akt/mTOR-mediated autophagy.ConclusionThis study provides multilevel evidence for the significance of E2F2 in the pathogenesis of GC and its potential as a biomarker for GC. E2F2 was highly expressed in GC, and high E2F2 expression was associated with the characteristics of invasive tumors and poor prognosis. E2F2 had potential modulatory effects on tumor immunity. We found a novel function of E2F2 in the regulation of PI3K/Akt/mTOR-mediated autophagy and the downstream process of cell migration and invasion. Our results may provide novel targets and strategies for the diagnosis and treatment of GC.