Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells

Abstract

Human cytomegalovirus (HCMV) infection has been implicated in epithelial ovarian cancer (OC). Polyploidy giant cancer cells (PGCCs) have been observed in high-grade serous ovarian carcinoma (HGSOC); they possess cancer stem cell-like characteristics and give rise to progeny cells expressing epithelial-mesenchymal transition (EMT) markers. EZH2 plays a potential oncogenic role, correlating with high proliferative index and tumor grade in OC. Herein, we present the experimental evidence for HCMV as a reprogramming vector that elicited human ovarian epithelial cells (OECs) transformation leading to the generation of “CMV-transformed Ovarian cells” (CTO). The infection with the two high-risk clinical strains, namely HCMV-DB and BL provoked a distinct cellular and molecular mechanisms in infected OECs. EZH2 upregulation and cellular proliferation were curtailed by using EZH2 inhibitors. The HGSOC biopsies were characterized by an elevated EZH2 expression, possessing a strong positive correlation between the aforementioned marker and HCMV. From HGSOC biopsies, we isolated three HCMV clinical strains that transformed OECs generating CTO cells which displayed proliferative potentials in addition to EZH2 upregulation and PGCCs generation; these features were reduced upon EZH2 inhibition. High-risk HCMV strains transformed OECs confirming an HCMV-induced epithelial ovarian cancer model and highlighting EZH2 tumorigenic properties. Our findings might be highly relevant in the pathophysiology of ovarian tumors thereby nominating new targeted therapeutics.

EZH2-Myc Hallmark in Oncovirus/Cytomegalovirus Infections and Cytomegalovirus’ Resemblance to Oncoviruses

“…The diverse roles of EZH2 in various biological processes contribute to its association with numerous diseases, notably cancer [ 18 , 20 ]. Studies provide evidence of elevated EZH2 expression in various cancer types, such as breast cancer, glioblastoma, ovarian cancer, gastric cancer, prostate cancer, esophageal cancer, anaplastic thyroid carcinoma, and nasopharyngeal carcinoma [ 14 , 15 , 16 , 17 , 19 ]. Due to its significant involvement in cancer pathophysiology, EZH2 emerges as a prospective target for treating cancer [ 19 , 20 ].…”

“…As previously mentioned, accumulating evidence underscores the pivotal roles of Myc and EZH2 in both oncogenesis and stemness. Following HCMV infection of human mammary epithelial cells (HMECs), ovarian epithelial cells (OECs), and astrocytes, a subtle activation of Myc and EZH2 as well as polyploidy induction were observed [ 15 , 16 , 71 ]. Myc overexpression can induce DNA replication, potentially leading to polyploidy [ 72 ].…”

“…This axis’ activation was notably detected in CMV-transformed HMECs (CTH), CMV-transformed OECs (CTO cells), and CMV-elicited glioblastoma cells (CEGBCs) exhibiting a significant increase in Myc and EZH2 proteins. The aforementioned cells were generated upon HCMV infection of HMECs, OECs, and HAs with high-risk oncogenic HCMV-DB and BL strains and strains isolated from breast cancer, high-grade serous ovarian carcinoma, and glioblastoma biopsies [ 14 , 15 , 16 , 71 , 74 ].…”

“…Several studies confirmed that HCMV infection has the potential to trigger Myc induction, foster stemness, and initiate pro-EZH2 pathways [ 14 , 15 , 16 ]. Interestingly, previous findings revealed that high-risk HCMV-BL and DB induced Myc expression, coupled with low p53 levels, which could stimulate the replicative potential of stem cells as well as progenitor reprogramming in breast cancer [ 14 , 71 ].…”

“…It enables tumors to evade immune responses by encoding viral proteins and promoting immunosuppressive cellular factors, establishing HCMV-induced immune tolerance that supports tumor growth [ 3 , 13 ]. Recently, it has been shown by our research group that the high-risk oncogenic HCMV strains have the capacity to induce Myc/EZH2 expression and induce the formation of polyploid giant cancer cells (PGCCs), suggesting a potential association between HCMV infection, elevated Myc/EZH2 expression, and polyploidy in vitro and in several tumors [ 14 , 15 , 16 , 17 ]. Collectively, our discoveries affirm the suggested tumorigenic properties of Enhancer of zeste homolog 2 (EZH2) and Myc upon HCMV infection.…”