Background and aim: The novel gene psiTPTE22-HERV identified by us previously is a human endogenous retrovirus (HERV)-related gene located adjacent to the gene psiTPTE22. With a high GC content around the promoter region, expression of psiTPTE22-HERV can be regulated epigentically by DNA methylation. We aimed to elucidate the clinical significance of epigenetic alteration and biological function of psiTPTE22-HERV in gastric cancer.
Methods and results: psiTPTE22-HERV was ubiquitously expressed in normal adult tissues including stomach, but was frequently silenced/down-reguated in gastric tumors and cancer cell lines as evidenced by RT-PCR. Bisulfite genomic sequencing results indicated that psiTPTE22-HERV was silenced by promoter DNA methylation, and its expression could be restored by demethylation treatments in gastric cancer cell lines. Ectopic expression of psiTPTE22-HERV significantly suppressed cell viability, clonogenicity and cell cycle progression, induced apoptosis, and inhibited migration and invasion of SGC7901 and MKN45 gastric cancer cells. In contrast, knock-down of psiTPTE22-HERV in the gastric cancer MKN1 cells significantly increased cell growth and migration ability, promoted cell cycle progress and inhibited cell apoptosis. psiTPTE22-HERV significantly suppressed subcutaneous tumorigenicity of SGC7901 cells in nude mice and metastasis (liver implantation) in tail vein injection models. Promoter methylation level of psiTPTE22-HERV was significantly higher in gastric tumors than in adjacent non-tumor tissues as revealed by bisulfite genomic sequencing (P<0.05); methylation levels in both tumors and adjacent non-tumor tissues of gastric cancer patients were significantly higher than in normal stomach tissues (both P<0.001). Multivariate Cox regression analysis demonstrated that promoter methylation of psiTPTE22-HERV in primary gastric tumors was an independent risk factor for poor survival. Kaplan-Meier survival curves showed that high-methylation of psiTPTE22-HERV promoter was significantly associated with shortened survival in gastric cancer patients from two independent cohorts (both P<0.05).
Conclusion: psiTPTE22-HERV functions as a tumor suppressor that is commonly down-regulated by promoter methylation in gastric cancer, which may serve as a prognostic biomarker for gastirc cancer patients.
Citation Format: Jessie Qiaoyi Liang, Fei Xu, Shu Zheng, Jun Yu. psiTPTE22-HERV functions as a tumor suppressor in gastric cancer and is associated with disease outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5519. doi:10.1158/1538-7445.AM2017-5519