SOX2 downregulation of PML increases HCMV gene expression and growth of glioma cells.
SOX2 downregulation of PML increases HCMV gene expression and growth of glioma cells.
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DOI：
10.1371/journal.ppat.1011316
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发表时间：
2023-04
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
人巨细胞病毒（HCMV）在胶质母细胞瘤（GBM）中的存在以及接受靶向病毒治疗的GBM患者的结局改善，表明HCMV参与了GBM进展。然而，一个统一的机制，占巨细胞病毒的恶性表型GBM的贡献仍然不完全确定。在这里，我们已经确定了SOX 2，胶质瘤干细胞（GSC）的标志物，作为一个关键的决定因素，HCMV基因表达的胶质瘤。我们的研究表明，SOX 2下调早幼粒细胞白血病（PML）和Sp100，从而促进病毒基因的表达，通过减少HCMV感染的胶质瘤细胞中PML核小体的数量。相反，PML的表达拮抗SOX 2对HCMV基因表达的影响。此外，在GSC的神经球测定和利用来自患者来源的神经胶质瘤组织的异种移植物的鼠异种移植物模型中证明了SOX 2对HCMV感染的这种调节。在这两种情况下，SOX 2过表达促进了植入免疫缺陷小鼠的神经球和异种移植物的生长。最后，SOX 2和HCMV立即早期1（IE 1）蛋白的表达可能与胶质瘤患者的组织相关，有趣的是，SOX 2和IE 1水平升高预示着更差的临床结果。这些研究认为，胶质瘤中的HCMV基因表达是由SOX 2通过其调节PML表达来调节的，并且该SOX 2-PML通路中的靶向分子可以鉴定用于胶质瘤治疗的疗法。巨细胞病毒与胶质瘤的发病机制有关，但目前对巨细胞病毒感染的分子特征研究还很缺乏，这阻碍了对巨细胞病毒如何促进胶质瘤进展的深入了解。我们鉴定了SOX 2-PML轴作为胶质瘤细胞中HCMV感染的关键调节因子，并在患者来源的异种移植小鼠模型中证明了SOX 2-PML轴不仅控制HCMV感染，而且有助于病毒的肿瘤调节作用。与这一发现相一致，神经胶质瘤中高水平的SOX 2和IE 1预示着更差的预后。据我们所知，这是胶质瘤细胞中HCMV感染的分子决定因素的首次报道，SOX 2-IE 1对可能作为一个有价值的预后因素，以分层胶质瘤患者的靶向分子治疗。
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. 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.
受感染的 T98G 胶质母细胞瘤细胞支持人巨细胞病毒从潜伏期重新激活
影响因子：
3.7
作者：
Cheng S;Jiang X;Yang B;Wen L;Zhao F;Zeng WB;Liu XJ;Dong X;Sun JY;Ming YZ;Zhu H;Rayner S;Tang Q;Fortunato E;Luo MH
通讯作者：
Luo MH
DOI：
10.3390/v9070175
发表时间：
2017-07-05
期刊：
Viruses
影响因子：
--
作者：
Martínez-Ramírez I;Del-Castillo-Falconi V;Mitre-Aguilar IB;Amador-Molina A;Carrillo-García A;Langley E;Zentella-Dehesa A;Soto-Reyes E;García-Carrancá A;Herrera LA;Lizano M
通讯作者：
Lizano M