Transcriptomics of HERVs reveals clinico-biological characterization of LTR5_Hs and HERVS71 loci in gastric cancer

Human endogenous retroviruses (HERVs), a type of endogenous transposable elements (ETE), have emerged as potential biomarkers and therapeutic targets for cancers. However, the transcriptional relevance of HERV elements in gastric cancer (GC) remains largely unexplored. This study aims to elucidate the interactions between locus-specific HERVs expression and clinical dynamics in GC patients. We compared HERVs locus-specific expression profiles from RNA sequencing of tumor and adjacent tissues, validated using the GEO database and RT-PCR. Analysis of dysregulated ETEs revealed 113 upregulated and 46 downregulated ETEs in tumor tissues compared to adjacent non-tumor tissues. Significant differences were found in HERVs clades such as HERVK, HERVS71, and HERVH. Four clinically relevant HERV elements-LTR5_Hs_1q22 and HERVS71_19q13.22 (int, rve, RNase_H)-were validated in serum samples via RT-PCR. Higher HERVs expression (HERVs^high) correlated with larger tumor size, higher grade, increased lymph node metastasis, and higher Odds ratio compared to lower expression (HERVs^low) groups. The diagnostic performance of the four HERV elements surpassed that of conventional biomarkers and improved with combined biomarker analysis. Differential and functional analysis indicated that these HERV elements significantly impacted the cell cycle, with their upregulation linked to tumor growth both in vitro and in vivo. Our exploration demonstrates the clinical significance of HERVs in tumor progression, highlighting their functional role and providing a valuable resource for developing new biomarkers and therapeutic targets in GC.