title: Human cytomegalovirus gene expression in long-term infected glioma stem cells.
abstract: 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.
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
authors.forename: Estefania
authors.initials: E
authors.lastname: Fiallos
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Judkins
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Matlaf
authors.affiliation: Department of Pediatrics and Infectious Disease, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Prichard
authors.affiliation: Department of Virology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Dirk
authors.initials: D
authors.lastname: Dittmer
authors.affiliation: The Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, Washington, United States of America; Department of Neurosurgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Cobbs
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
authors.forename: Liliana
authors.initials: L
authors.lastname: Soroceanu
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000235:genetics; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000821:virology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000821:virology*; D015398:Signal Transduction / Q000187:drug effects; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D015850:Interleukin-6; D014764:Viral Proteins