EZH2-Myc driven glioblastoma elicited by cytomegalovirus infection of human astrocytes

被引:21
作者
El Baba, Ranim [1 ]
Pasquereau, Sebastien [1 ]
Ahmad, Sandy Haidar [1 ]
Monnien, Franck [2 ]
Abad, Marine [2 ]
Bibeau, Frederic [2 ]
Herbein, Georges [1 ,3 ]
机构
[1] Univ Franche Comte, Dept Pathogens & Inflammat, EPILAB Lab, EA4266, Besancon, France
[2] CHU Besancon, Dept Pathol, Besancon, France
[3] CHU Besancon, Dept Virol, Besancon, France
关键词
ANTIVIRAL DRUG GANCICLOVIR; STEM-CELL; POTENT INHIBITOR; EXPRESSION; GLIOMA; DIFFERENTIATION; PROLIFERATION;
D O I
10.1038/s41388-023-02709-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mounting evidence is identifying human cytomegalovirus (HCMV) as a potential oncogenic virus. HCMV has been detected in malignant gliomas. EZH2 and Myc play a potential oncogenic role, correlating with the glioma grade. Herewith, we present the first experimental evidence for HCMV as a reprogramming vector, straight through the dedifferentiation of mature human astrocytes, and generation of CMV-Elicited Glioblastoma Cells (CEGBCs) possessing glioblastoma-like traits. HCMV counterparts the progression of the perceived cellular and molecular mechanisms succeeding the transformation and invasion processes with CEGBCs involved in spheroid formation and invasiveness. Glioblastoma multiforme (GBM) biopsies were characterized by an elevated EZH2 and Myc expression, possessing a strong positive correlation between the aforementioned markers in the presence of HCMV. From GBM tissues, we isolated HCMV clinical strains that transformed HAs toward CEGBCs exhibiting upregulated EZH2 and Myc. Spheroids generated from CEGBCs possessed invasion potential and were sensitive to EZH2 inhibitor, ganciclovir, and temozolomide triple therapy. HCMV clinical strains transform HAs and fit with an HCMV-induced glioblastoma model of oncogenesis, and supports the tumorigenic properties of Myc and EZH2 which might be highly pertinent in the pathophysiology of astrocytic brain tumors and thereby paving the way for new therapeutic strategies.
引用
收藏
页码:2031 / 2045
页数:15
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