Cytomegalovirus infection of glioblastoma cells leads to NF-κB dependent upregulation of the c-MET oncogenic tyrosine kinase.
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.
['Krenzlin|Harald|H|', 'Zdioruk|Mykola|M|', 'Nowicki|Michal O|MO|', 'Finkelberg|Tomer|T|', 'Keric|Naureen|N|', 'Lemmermann|Niels|N|', 'Skubal|Magdalena|M|', 'Chiocca|E Antonio|EA|', 'Cook|Charles H|CH|', 'Lawler|Sean E|SE|']
D000818:Animals D001932:Brain Neoplasms D003586:Cytomegalovirus Infections D005909:Glioblastoma D006801:Humans D051379:Mice D016328:NF-kappa B D019859:Proto-Oncogene Proteins c-met D015854:Up-Regulation
Cytomegalovirus Glioblastoma NF-κB c-MET