Gastric cancer is a major cause of cancer mortality, with epigenetic silencing of tumor-suppressor genes playing a central role in its pathogenesis. The role of psiTPTE22-HERV, a recently evolved human-specific gene resulting from the fusion of human endogenous retrovirus (HERV) DNA and adjacent non-HERV DNA, in gastric carcinogenesis has remained unclear.
In this study published in Genes & Diseases, researchers from Zhejiang University School of Medicine and The Chinese University of Hong Kong investigated the epigenetic regulation, biological functions, molecular mechanisms, and clinical significance of psiTPTE22-HERV in gastric cancer.

Using TCGA data, bisulfite genomic sequencing, and patient sample evaluations, the authors showed that psiTPTE22-HERV is widely expressed in normal tissues but consistently down-regulated across multiple primary tumors. Furthermore, the authors identified promoter hypermethylation at specific CpG sites as a mechanism underlying psiTPTE22-HERV suppression in gastric cancer. In gastric cancer tissue samples and clinical cohorts, psiTPTE22-HERV showed a progressive decline from normal gastric mucosa to adjacent non-tumor tissues and primary tumors, and its reduced expression was significantly associated with advancing TNM stage and poor patient prognosis.

Building upon these clinical observations, in vitro gain- and loss-of-function assays revealed that ectopic overexpression of psiTPTE22-HERV inhibited cancer cell viability, clonogenicity, migration, invasion, and epithelial–mesenchymal transition, as evidenced by increased E-cadherin and reduced mesenchymal markers, while inducing G1-S cell cycle arrest and apoptosis. Conversely, its siRNA-mediated knockdown enhanced these malignant behaviors. These findings were further validated in in vivo subcutaneous xenograft and tail-vein injection mouse models, which showed that stable psiTPTE22-HERV expression inhibited xenograft growth and reduced liver and lung metastases.

RNA-seq and GSEA revealed that psiTPTE22-HERV alters protein-synthesis-related processes and inhibits PI3K/AKT/mTOR signaling. Specifically, western blotting and correlation analyses confirmed that psiTPTE22-HERV exerts its tumor-suppressive effects by inhibiting the PI3K/AKT/mTOR signaling axis, thereby downregulating the downstream effectors EIF4EBP1, phosphorylated EIF4EBP1 at Thr70, and cytoplasmic EIF4E.

The authors acknowledge that a lack of reliable antibodies currently limits direct characterization of the endogenous psiTPTE22-HERV protein and identification of its interacting molecules. Nevertheless, these multilevel findings establish that psiTPTE22-HERV functions as an epigenetically silenced tumor suppressor.

Collectively, this study identifies psiTPTE22-HERV as a methylation-silenced tumor suppressor that restrains gastric cancer growth and metastasis by inhibiting the PI3K/AKT/mTOR/EIF4E axis, highlighting its potential as a prognostic biomarker and therapeutic target.

Reference
Title of the original paper: psiTPTE22-HERV functions as a tumor suppressor by inhibiting PI3K/AKT/mTOR/EIF4E signaling
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101915

Funding Information:
Noncommunicable Chronic Diseases-National Science and Technology Major Project (China) (No. 2023ZD0501400)
National Natural Science Foundation of China (No. 81773000)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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