U94/rep of human herpesvirus 6 inhibits proliferation, invasion, and angiogenesis of glioma

Abstract

Purpose: We previously found the involvement of human herpesvirus 6 (HHV-6) infection in the pathogenesis of glioma. U94/rep, encoded by HHV-6, has been identified to play a vital role in viral gene expression and latency. Recent studies have shown its inhibition of angiogenesis and tumorigenesis in endothelial cells and prostate cancer cell line PC3, respectively. Here, we aimed to investigate the role of U94/rep in the development and progression of glioma. Patients and methods: A total of 20 glioma tissues with positive HHV-6 infection were used for detection of U94/rep. MTT, soft agar, propidium iodide staining, wound healing, Transwell, and chick embryo chorioallantoic membrane assays were applied for evaluation of glioma cells’ proliferation, colony formation, cell cycle, migration, invasion, and angiogenesis, respectively. Results: U94/rep transcripts could be detected in 11 out of 20 glioma tissues with positive HHV-6 infection. Furthermore, MTT and soft agar assays revealed that overexpression of U94/ rep inhibited glioma cell proliferation and colony formation, which may be attributed to the cell cycle arrest at S phase induced by U94/rep. Further analysis demonstrated that U94/rep inhibited glioma cells’ migration and invasion and ex vivo angiogenesis. Reduced expression of proangiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, and type IV collagenases, MMP-2 and MMP-9, was detected in cells overexpressing U94/rep. These decreased factors may undermine glioma cell migration, invasion, and angiogenesis. Conclusion: Our results demonstrated that U94/rep could inhibit malignant phenotypes of glioma cells, indicating that it is a potential target for therapeutic intervention.