El Baba Ranim, Haidar Ahmad Sandy, Monnien Franck, Mansar Racha, Bibeau Frédéric, Herbein Georges
Department of Pathogens & Inflammation-EPILAB Laboratory EA4266, University of Franche-Comté, Besançon, France.
Department of Pathology, CHU Besançon, Besançon, France.
Oncogene. 2023 Oct;42(41):3047-3061. doi: 10.1038/s41388-023-02813-4. Epub 2023 Aug 26.
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.
人巨细胞病毒（HCMV）感染与上皮性卵巢癌（OC）有关。在高级别浆液性卵巢癌（HGSOC）中已观察到多倍体巨癌细胞（PGCCs）；它们具有癌症干细胞样特征，并产生表达上皮-间质转化（EMT）标志物的子代细胞。EZH2发挥潜在的致癌作用，与OC中的高增殖指数和肿瘤分级相关。在此，我们提供了实验证据，证明HCMV作为一种重编程载体，可引发人卵巢上皮细胞（OECs）转化，导致“CMV转化的卵巢细胞”（CTO）的产生。用两种高风险临床株，即HCMV-DB和BL感染，在受感染的OECs中引发了独特的细胞和分子机制。使用EZH2抑制剂可减少EZH2上调和细胞增殖。HGSOC活检的特征是EZH2表达升高，上述标志物与HCMV之间呈强正相关。从HGSOC活检中，我们分离出三种HCMV临床株，它们转化OECs产生CTO细胞，这些细胞除了EZH2上调和PGCCs产生外，还显示出增殖潜力；EZH2抑制后，这些特征减弱。高风险HCMV株转化OECs，证实了HCMV诱导的上皮性卵巢癌模型，并突出了EZH2的致瘤特性。我们的发现可能与卵巢肿瘤的病理生理学高度相关，从而为新的靶向治疗提供依据。
