Human Cytomegalovirus Gene Expression in Long-Term Infected Glioma Stem Cells
Human Cytomegalovirus Gene Expression in Long-Term Infected Glioma Stem Cells
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DOI：
10.1371/journal.pone.0116178
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发表时间：
2014-12-30
期刊：
影响因子：
3.7
通讯作者：
Soroceanu, Liliana
中科院分区：
文献类型：
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作者：
Fiallos, Estefania;Judkins, Jonathon;Soroceanu, Liliana
最常见的成人原发性脑肿瘤，胶质母细胞瘤（GBM），其特征在于15个月的中位患者生存期，并且没有明确的病因。我们和其他人已经确定了存在的人巨细胞病毒（HCMV）基因产物内源性表达的GBM组织和原代细胞，与一个子集的病毒基因一致表达在大多数样品。在这些病毒基因中，有几个具有重要的肿瘤调节特性，调节肿瘤的干性、增殖、免疫逃避、侵袭和血管生成。这些发现使我们推测，一个特定的HCMV基因签名可能与GBM的发病机制。为了研究这一假设，我们使用神经胶质瘤细胞系和原代神经胶质瘤干细胞样细胞（GSC）感染的临床和实验室HCMV株，并测量相对病毒基因表达水平沿着几个时间点，直到15周后感染。虽然在感染后5周在几个感染的胶质瘤细胞系中检测到HCMV基因表达，但只有HCMV感染的GSC在感染后15周表达病毒基因产物。与细胞系相比，在GSC中跨时间的感染效率更高。重要的是，HCMV感染的GSC比未感染的GSC活得长，这种延长的生存期是由肿瘤球频率增加和干性调节因子如SOX 2、p-STAT 3和BMX（本研究中鉴定的一种新的HCMV靶点）上调引起的。白细胞介素6（IL-6）治疗显着上调HCMV基因的表达在长期感染的神经胶质瘤培养，表明在肿瘤环境中的促炎信号可能会进一步增加HCMV基因的表达和随后的肿瘤进展驱动的病毒诱导的细胞信号。总之，我们的数据支持长期、低水平HCMV感染在促进GSC存活、干性和增殖方面的关键作用，这可能显著促进GBM发病机制。
The most common adult primary brain tumor, glioblastoma (GBM), is characterized by fifteen months median patient survival and has no clear etiology. We and others have identified the presence of human cytomegalovirus (HCMV) gene products endogenously expressed in GBM tissue and primary cells, with a subset of viral genes being consistently expressed in most samples. Among these viral genes, several have important oncomodulatory properties, regulating tumor stemness, proliferation, immune evasion, invasion and angiogenesis. These findings lead us to hypothesize that a specific HCMV gene signature may be associated with GBM pathogenesis. To investigate this hypothesis, we used glioma cell lines and primary glioma stem-like cells (GSC) infected with clinical and laboratory HCMV strains and measured relative viral gene expression levels along several time points up to 15 weeks post-infection. While HCMV gene expression was detected in several infected glioma lines through week 5 post-infection, only HCMV-infected GSC expressed viral gene products 15 weeks post-infection. Efficiency of infection across time was higher in GSC compared to cell lines. Importantly, HCMV-infected GSC outlived their uninfected counterparts, and this extended survival was paralleled by increased tumorsphere frequency and upregulation of stemness regulators, such as SOX2, p-STAT3, and BMX (a novel HCMV target identified in this study). Interleukin 6 (IL-6) treatment significantly upregulated HCMV gene expression in long-term infected glioma cultures, suggesting that pro-inflammatory signaling in the tumor milieu may further augment HCMV gene expression and subsequent tumor progression driven by viral-induced cellular signaling. Together, our data support a critical role for long-term, low-level HCMV infection in promoting survival, stemness, and proliferation of GSC that could significantly contribute to GBM pathogenesis.