title: Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma.
abstract: Glioblastoma (GBM) is the most common and aggressive human brain tumor. Human cytomegalovirus (HCMV) immediate-early (IE) proteins that are endogenously expressed in GBM cells are strong viral transactivators with oncogenic properties. Here, we show how HCMV IEs are preferentially expressed in glioma stem-like cells (GSC), where they colocalize with the other GBM stemness markers, CD133, Nestin, and Sox2. In patient-derived GSCs that are endogenously infected with HCMV, attenuating IE expression by an RNAi-based strategy was sufficient to inhibit tumorsphere formation, Sox2 expression, cell-cycle progression, and cell survival. Conversely, HCMV infection of HMCV-negative GSCs elicited robust self-renewal and proliferation of cells that could be partially reversed by IE attenuation. In HCMV-positive GSCs, IE attenuation induced a molecular program characterized by enhanced expression of mesenchymal markers and proinflammatory cytokines, resembling the therapeutically resistant GBM phenotype. Mechanistically, HCMV/IE regulation of Sox2 occurred via inhibition of miR-145, a negative regulator of Sox2 protein expression. In a spontaneous mouse model of glioma, ectopic expression of the IE1 gene (UL123) specifically increased Sox2 and Nestin levels in the IE1-positive tumors, upregulating stemness and proliferation markers in vivo. Similarly, human GSCs infected with the HCMV strain Towne but not the IE1-deficient strain CR208 showed enhanced growth as tumorspheres and intracranial tumor xenografts, compared with mock-infected human GSCs. Overall, our findings offer new mechanistic insights into how HCMV/IE control stemness properties in GBM cells.
authors.affiliation: Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California. sorocel@cpmcri.org charles.cobbs@gmail.com.
authors.forename: Liliana
authors.initials: L
authors.lastname: Soroceanu
authors.affiliation: Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California.
authors.forename: Lisa
authors.initials: L
authors.lastname: Matlaf
authors.affiliation: Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California.
authors.forename: Sabeena
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California.
authors.forename: Armin
authors.initials: A
authors.lastname: Akhavan
authors.affiliation: Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Singer
authors.affiliation: Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bezrookove
authors.affiliation: Department of Pediatrics and Neurosurgery, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
authors.forename: Stacy
authors.initials: S
authors.lastname: Decker
authors.affiliation: Center for Applied Genomics, Institute of Genomic Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey.
authors.forename: Saleena
authors.initials: S
authors.lastname: Ghanny
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Piotr
authors.initials: P
authors.lastname: Hadaczek
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, California.
authors.forename: Henrik
authors.initials: H
authors.lastname: Bengtsson
authors.affiliation: Department of Pediatrics and Neurosurgery, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
authors.forename: John
authors.initials: J
authors.lastname: Ohlfest
authors.affiliation: Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California.
authors.forename: Maria-Gloria
authors.initials: MG
authors.lastname: Luciani-Torres
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Lualhati
authors.initials: L
authors.lastname: Harkins
authors.affiliation: Department of Pathology, University of California, San Francisco, California.
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.affiliation: Center for Applied Genomics, Institute of Genomic Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey.
authors.forename: Hong
authors.initials: H
authors.lastname: Guo
authors.affiliation: Center for Applied Genomics, Institute of Genomic Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey.
authors.forename: Patricia
authors.initials: P
authors.lastname: Soteropoulos
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Seattle, Washington. sorocel@cpmcri.org charles.cobbs@gmail.com.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Cobbs
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D003587:Cytomegalovirus / Q000235:genetics / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000473:pathology; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D005910:Glioma / Q000235:genetics / Q000473:pathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000821:virology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000956:Antigens, Viral; C088645:IE1 protein, cytomegalovirus; D017874:Immediate-Early Proteins; C561122:MIRN154 microRNA, human; D035683:MicroRNAs; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C044582:immediate-early proteins, cytomegalovirus