Krenzlin Harald, Zdioruk Mykola, Nowicki Michal O, Finkelberg Tomer, Keric Naureen, Lemmermann Niels, Skubal Magdalena, Chiocca E Antonio, Cook Charles H, Lawler Sean E
Harvey Cushing Neurooncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurosurgery, University Hospital Mainz, Gutenberg University, Mainz, Germany.
Harvey Cushing Neurooncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Cancer Lett. 2021 Aug 10;513:26-35. doi: 10.1016/j.canlet.2021.05.005. Epub 2021 May 12.
Cytomegalovirus (CMV) is widespread in humans and has been implicated in glioblastoma (GBM) and other tumors. However, the role of CMV in GBM remains poorly understood and the mechanisms involved are not well-defined. The goal of this study was to identify candidate pathways relevant to GBM that may be modulated by CMV. Analysis of RNAseq data after CMV infection of patient-derived GBM cells showed significant upregulation of GBM-associated transcripts including the MET oncogene, which is known to play a role in a subset of GBM patients. These findings were validated in vitro in both mouse and human GBM cells. Using immunostaining and RT-PCR in vivo, we confirmed c-MET upregulation in a mouse model of CMV-driven GBM progression and in human GBM. siRNA knockdown showed that MET upregulation was dependent on CMV-induced upregulation of NF-κB signaling. Finally, proneural GBM xenografts overexpressing c-MET grew much faster in vivo than controls, suggesting a mechanism by which CMV infection of tumor cells could induce a more aggressive mesenchymal phenotype. These studies implicate the CMV-induced upregulation of c-MET as a potential mechanism involved in the effects of CMV on GBM growth.
巨细胞病毒（CMV）在人类中广泛存在，并与胶质母细胞瘤（GBM）及其他肿瘤有关。然而，CMV在GBM中的作用仍知之甚少，其涉及的机制也尚未明确。本研究的目的是确定与GBM相关的、可能受CMV调节的候选通路。对患者来源的GBM细胞进行CMV感染后的RNA测序数据分析显示，包括MET癌基因在内的GBM相关转录本显著上调，已知MET癌基因在一部分GBM患者中发挥作用。这些发现在小鼠和人类GBM细胞的体外实验中得到了验证。通过体内免疫染色和逆转录-聚合酶链反应（RT-PCR），我们在CMV驱动的GBM进展小鼠模型和人类GBM中证实了c-MET的上调。小干扰RNA（siRNA）敲低实验表明，MET的上调依赖于CMV诱导的核因子κB（NF-κB）信号通路的上调。最后，过表达c-MET的神经干细胞样GBM异种移植瘤在体内生长速度比对照快得多，这表明肿瘤细胞的CMV感染可能诱导更具侵袭性的间充质表型的一种机制。这些研究表明，CMV诱导的c-MET上调是CMV影响GBM生长的潜在机制之一。
