SOX2 downregulation of PML increases HCMV gene expression and growth of glioma cells.

Autor: Wen, Le, Wang, Xian-Zhang, Qiu, Yong, Zhou, Yue-Peng, Zhang, Qing-Yang, Cheng, Shuang, Sun, Jin-Yan, Jiang, Xing-Jun, Rayner, Simon, Britt, William J., Chen, Jian, Hu, Fei, Li, Fang-Cheng, Luo, Min-Hua, Cheng, Han
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Zdroj: PLoS Pathogens; 4/14/2023, Vol. 18 Issue 4, p1-27, 27p
Abstrakt: The presence of human cytomegalovirus (HCMV) in glioblastoma (GBM) and improved outcomes of GBM patients receiving therapies targeting the virus have implicated HCMV in GBM progression. However, a unifying mechanism that accounts for the contribution of HCMV to the malignant phenotype of GBM remains incompletely defined. Here we have identified SOX2, a marker of glioma stem cells (GSCs), as a key determinant of HCMV gene expression in gliomas. Our studies demonstrated that SOX2 downregulated promyelocytic leukemia (PML) and Sp100 and consequently facilitated viral gene expression by decreasing the amount of PML nuclear bodies in HCMV-infected glioma cells. Conversely, the expression of PML antagonized the effects of SOX2 on HCMV gene expression. Furthermore, this regulation of SOX2 on HCMV infection was demonstrated in a neurosphere assay of GSCs and in a murine xenograft model utilizing xenografts from patient-derived glioma tissue. In both cases, SOX2 overexpression facilitated the growth of neurospheres and xenografts implanted in immunodeficient mice. Lastly, the expression of SOX2 and HCMV immediate early 1 (IE1) protein could be correlated in tissues from glioma patients, and interestingly, elevated levels of SOX2 and IE1 were predictive of a worse clinical outcome. These studies argue that HCMV gene expression in gliomas is regulated by SOX2 through its regulation of PML expression and that targeting molecules in this SOX2-PML pathway could identify therapies for glioma treatment. Author summary: HCMV has been implicated in glioma pathogenesis, but the molecular characterization of the infection is completely lacking, hindering a thorough understanding of how HCMV contributes to glioma progression. We identified the SOX2-PML axis as a key regulator of HCMV infection in glioma cells and demonstrated in a patient-derived xenograft mouse model that the SOX2-PML axis not only controls HCMV infection but also contributes to the oncomodulatory role of the virus. Consistent with this finding, high levels of SOX2 and IE1 in gliomas predict a worse prognosis. To our knowledge, this is the first report of molecular determinants of HCMV infection in glioma cells, and the SOX2-IE1 pair may serve as a valuable prognostic factor to stratify glioma patients for targeted molecular therapies. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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