Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma.
Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma.
复制标题
DOI：
10.1158/0008-5472.can-14-3307
复制
发表时间：
2015-08-01
期刊：
影响因子：
11.2
通讯作者：
Cobbs CS
中科院分区：
文献类型：
--
作者：
Soroceanu L;Matlaf L;Khan S;Akhavan A;Singer E;Bezrookove V;Decker S;Ghanny S;Hadaczek P;Bengtsson H;Ohlfest J;Luciani-Torres MG;Harkins L;Perry A;Guo H;Soteropoulos P;Cobbs CS
胶质母细胞瘤（GBM）是最常见和侵袭性的人类脑肿瘤。人巨细胞病毒（HCMV）即时早期（IE）蛋白在GBM细胞中内源性表达，是具有致癌特性的强病毒反激活因子。在这里，我们展示了HCMV IE如何优先在胶质瘤干细胞样细胞（GSC）中表达，在那里它们与其他GBM干细胞标记物CD133、Nestin和Sox2共定位。在内源性感染HCMV的患者源性GSC中，通过基于rna -i的策略减弱IE表达，足以抑制肿瘤球形成、Sox2表达、细胞周期进展和细胞存活。相反，HCMV感染hmcv阴性的GSC会引起细胞的强大自我更新和增殖，这可以通过IE衰减部分逆转。在hcmv阳性的GSC中，IE衰减诱导了一个以间充质标记物和促炎细胞因子表达增强为特征的分子程序，类似于治疗抗性GBM表型。从机制上讲，HCMV/IE通过抑制miRNA-145 （Sox2蛋白表达的负调节因子）来调控Sox2。在自发性胶质瘤小鼠模型中，IE1基因（UL123）的异位表达特异性地增加了IE1阳性肿瘤中Sox2和Nestin的水平，上调了体内的干性和增殖标志物。同样，与模拟感染的人GSC相比，感染HCMV菌株Towne而不感染ie1缺陷菌株CR208的人GSC表现出肿瘤球和颅内肿瘤异种移植物的生长增强。总的来说，我们的发现为HCMV/IE如何控制胶质母细胞瘤细胞的干细胞特性提供了新的机制见解。
Glioblastoma (GBM) is the most common and aggressive human brain tumor. Human cytomegalovirus (HCMV) immediate early (IE) proteins that are endogenously expressed in GBM cells are strong viral transactivators with onconcogenic properties. Here, we show how HCMV IE are preferentially expressed in glioma stem-like cells (GSC), where they co-localize with the other GBM stemness markers, CD133, Nestin, and Sox2. In patient-derived GSC that are endogenously infected with HCMV, attenuating IE expression by an RNA-i-based strategy, was sufficient to inhibit tumorsphere formation, Sox2 expression, cell cycle progression, and cell survival. Conversely, HCMV infection of HMCV-negative GSC elicited robust self-renewal and proliferation of cells that could be partially reversed by IE attenuation. In HCMV-positive GSC, IE attenuation induced a molecular program characterized by enhanced expression of mesenchymal markers and pro-inflammatory cytokines, resembling the therapeutically-resistant GBM phenotype. Mechanistically, HCMV/IE regulation of Sox2 occurred via inhibition of miRNA-145, a negative regulator of Sox2 protein expression. In a spontaneous mouse model of glioma, ectopic expression of the IE1 gene (UL123) specifically increased Sox2 and Nestin levels in the IE1-positive tumors, upregulating stemness and proliferation markers in vivo. Similarly, human GSC infected with the HCMV strain Towne but not the IE1-deficient strain CR208 showed enhanced growth as tumorspheres and intracranial tumor xenografts, compared to mock-infected human GSC. Overall, our findings offer new mechanistic insights into how HCMV/IE control stemness properties in glioblastoma cells.