Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype.
Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype.
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DOI：
10.1158/0008-5472.can-11-0744
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发表时间：
2011-11-01
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;Bezrookove V;Harkins L;Martinez R;Greene M;Soteropoulos P;Cobbs CS
人巨细胞病毒（HCMV）感染常见于多形性胶质母细胞瘤（GBM）肿瘤，但病毒是否有助于GBM发病机制尚不清楚。在这项研究中，我们探讨了G蛋白偶联受体样蛋白US 28编码的HCMV，我们发现在人类GBM广泛表达的致癌作用。免疫组织化学和RT-PCR方法确定US 28在约60%的人GBM组织和原代培养物中表达。在未感染的GBM细胞或被认为是GBM前体细胞的神经祖细胞中，HCMV感染或US 28过表达足以促进生物活性VEGF的分泌并激活多种促进胶质瘤生长和侵袭的细胞激酶，包括磷酸化STAT 3和e-NOS。与这些发现一致，US 28过表达增加了基质胶中的原代GBM细胞侵袭。值得注意的是，这种侵袭性表型通过暴露于RANTES/CCL 5（一种US 28配体）而进一步增强，与GBM中的不良患者结局相关。相反，在持续感染HCMV的人脑胶质瘤细胞中，RNAi介导的US 28敲低导致响应于CCL 5刺激的VEGF表达和胶质瘤细胞侵袭的抑制。对临床GBM标本的分析进一步揭示，US 28与血管生成和炎症的几种标志物（包括VEGF、p-STAT 3、COX 2和e-NOS）原位共定位。综上所述，我们的结果表明，US 28从HCMV的表达有助于GBM的发病机制，通过诱导侵入性，血管生成表型。此外，这些发现认为US 28-CCL 5旁分泌信号可能有助于胶质瘤进展，并且它们表明靶向US 28可能在GBM治疗中提供治疗益处。
Human cytomegalovirus (HCMV) infections are seen often in glioblastoma multiforme (GBM) tumors, but whether the virus contributes to GBM pathogenesis is unclear. In this study, we explored an oncogenic role for the G protein-coupled receptor-like protein US28 encoded by HCMV that we found to be expressed widely in human GBMs. Immunohistochemical and RT-PCR approaches established that US28 was expressed in ~60% of human GBM tissues and primary cultures examined. In either uninfected GBM cells or neural progenitor cells, thought to be the GBM precursor cells, HCMV infection or US28 overexpression was sufficient to promote secretion of biologically active VEGF and to activate multiple cellular kinases which promote glioma growth and invasion, including phosphorylated STAT3 and e-NOS. Consistent with these findings, US28 overexpression increased primary GBM cell invasion in Matrigel. Notably, this invasive phenotype was further enhanced by exposure to RANTES/CCL5, a US28 ligand, associated with poor patient outcome in GBM. Conversely, RNAi-mediated knockdown of US28 in human glioma cells persistently infected with HCMV led to an inhibition in VEGF expression and glioma cell invasion in response to CCL5 stimulation. Analysis of clinical GBM specimens further revealed that US28 co-localized in situ with several markers of angiogenesis and inflammation, including VEGF, p-STAT3, COX2 and e-NOS. Taken together, our results indicate that US28 expression from HCMV contributes to GBM pathogenesis by inducing an invasive, angiogenic phenotype. Additionally, these findings argue that US28-CCL5 paracrine signaling may contribute to glioma progression and they suggest that targeting US28 may provide therapeutic benefits in GBM treatment.