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Cancer Res. 2015 Aug 1;75(15):3065-76. doi: 10.1158/0008-5472.CAN-14-3307.

Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma.

Author information

1
Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California. sorocel@cpmcri.org charles.cobbs@gmail.com.
2
Department of Neurosciences, California Pacific Medical Center Research Institute, San Francisco, California.
3
Department of Pediatrics and Neurosurgery, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
4
Center for Applied Genomics, Institute of Genomic Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey.
5
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
6
Department of Epidemiology and Biostatistics, University of California, San Francisco, California.
7
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
8
Department of Pathology, University of California, San Francisco, California.
9
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.

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.

PMID:
26239477
PMCID:
PMC4526117
DOI:
10.1158/0008-5472.CAN-14-3307
[Indexed for MEDLINE]
Free PMC Article

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