Formation of polyploid giant cancer cells and the transformative role of human cytomegalovirus IE1 protein

Abstract

Human cytomegalovirus (HCMV) infection has been linked to various cancers, including glioblastoma (GB), breast cancer (BC), and ovarian epithelial cancer (OC) especially high grade serous ovarian cancer (HGSOC). HCMV gene products control tumorigenic cellular pathways and processes associated with all the hallmarks of cancer. Among the suspected HCMV proteins involved in cellular transformation, the immediate early-1 (IE1) protein stands out as a significant player. Herein, we presented the experimental evidence supporting HCMV-IE1 role as a reprogramming factor that induces the transformation of human ovarian epithelial cells (OECs) resulting in the generation of "CMV transformed ovarian epithelial cells-IE1″ or CTO-IE1. These transformed cells exhibit similarities to those previously reported by our group, following infection with the high-risk oncogenic HCMV strain DB. HCMV-IE1-DB protein triggered distinct cellular and molecular mechanisms in stably transduced OECs. This included downregulation of Rb/p53 and upregulation of Myc/EZH2, concurrent with the emergence of polyploid giant cancer cells (PGCCs) and giant cell cycling in the culture. HCMV-IE1-DB silencing limited cellular transformation and stemness. In HGSOC, PGCCs were detected in the presence of IE1; the latter positively correlated with Myc. In addition, HCMV IE1 exhibits transforming capabilities in human mammary epithelial cells (HMECs) and human astrocytes (HAs) in vitro, reflecting its potential role in the transformation observed in vivo. This highlights the tumorigenic properties of Myc/EZH2 in the context of IE1-mediated transformation parallel to PGCCs appearance.

Keywords: Breast cancer; CMV-Transformed cells; Cytomegalovirus; Glioblastoma; High-grade serous ovarian carcinoma; Immediate-early 1 protein; PGCCs.