psiTPTE22-HERV functions as a tumor suppressor by inhibiting PI3K/AKT/mTOR/EIF4E signaling

psiTPTE22-HERV is a human-specific gene with unexplored functions. This study investigated its regulation, molecular mechanism, and clinical significance in gastric cancer. psiTPTE22-HERV expression was consistently down-regulated in primary tumors and cancer cell lines across various cancer types, including gastric cancer, as indicated by TCGA data and quantitative PCR analysis. Its down-regulation in gastric cancer cells is mediated by promoter methylation, confirmed through bisulfite genomic sequencing, with expression restored following demethylation treatment. A progressive reduction in psiTPTE22-HERV expression was observed from normal stomach mucosa to adjacent non-tumor tissues and primary tumors ( P < 0.05), along with increased methylation ( P < 0.0001). Gain- and loss-of-function assays revealed that psiTPTE22-HERV inhibited cancer cell viability, clonogenicity, cell cycle progression, migration, and invasion while promoting apoptosis. It also suppressed subcutaneous tumor growth and distant metastasis in mice. Transcriptomic analysis revealed that psiTPTE22-HERV disrupted PI3K/AKT/mTOR signaling. Western blotting confirmed that psiTPTE22-HERV reduced protein levels of PI3K, p-AKT, and mTOR. This led to the down-regulation of EIF4E and EIF4EBP1, oncogenic protein synthesis genes and effectors of mTOR signaling, as well as p-EIF4EBP1(Thr70), which is regulated by mTOR. Notably, psiTPTE22-HERV expression was inversely correlated with EIF4E, EIF4EBP1, and p-EIF4EBP1 (Thr70) in gastric tumors (all P < 0.001). Multivariate analysis revealed that psiTPTE22-HERV expression in primary gastric tumors independently predicted survival ( P = 0.027). Kaplan–Meier survival analysis showed that low psiTPTE22-HERV expression was significantly associated with shortened survival in gastric cancer patients ( P = 0.0009). Overall, psiTPTE22-HERV plays a tumor-suppressive role by inhibiting the PI3K/AKT/mTOR/EIF4E pathway, and its down-regulation serves as an independent marker for poor prognosis in gastric cancer patients.