1. Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma.
- Author
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Soroceanu L, Matlaf L, Khan S, Akhavan A, Singer E, Bezrookove V, Decker S, Ghanny S, Hadaczek P, Bengtsson H, Ohlfest J, Luciani-Torres MG, Harkins L, Perry A, Guo H, Soteropoulos P, and Cobbs CS
- Subjects
- Animals, Antigens, Viral genetics, Apoptosis genetics, Brain Neoplasms metabolism, Cytomegalovirus genetics, Cytomegalovirus pathogenicity, Cytomegalovirus Infections pathology, Disease Models, Animal, Gene Knockdown Techniques, Glioblastoma metabolism, Glioma genetics, Glioma pathology, Humans, Immediate-Early Proteins genetics, Mice, Inbred BALB C, MicroRNAs genetics, MicroRNAs metabolism, Neoplastic Stem Cells pathology, Neoplastic Stem Cells virology, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Tumor Cells, Cultured, Antigens, Viral metabolism, Brain Neoplasms pathology, Brain Neoplasms virology, Glioblastoma pathology, Glioblastoma virology, Immediate-Early Proteins metabolism
- 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., (©2015 American Association for Cancer Research.) more...
- Published
- 2015
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