| Popis: |
Glioblastoma (GBM), the most aggressive primary brain tumors, are categorized into the major subgroups: proneural, neural, classical and mesenchymal, the latter being characterized by increased invasion and poor prognosis. We recently identified RTVP-1 as a glioma-associated protein that regulates glioma cell migration and invasion. Using ChiP analyses, we found that the RTVP-1 promoter binds STAT3 and C/EBPbeta, the two master transcription factors that regulate mesenchymal transformation of GBM. Analysis of TCGA tumor specimens demonstrated that the expression of RTVP-1 was higher in the mesenchymal GBM and was inversely correlated with patient survival. We further found that RTVP-1 was expressed in glioma stem cells (GSCs) but not in human neural stem cells (NSCs). Overexpression of RTVP-1 in NSCs induced their mesenchymal transformation, whereas silencing of RTVP-1 in GSCs decreased their mesenchymal signature, increased their neural phenotypes and inhibited the self renewal and stemness of these cells. Silencing of RTVP-1 also decreased tumor volume of GSC-derived xenografts and increased animal survival. Using gene array analysis of RTVP-1 silenced cells we identified IL-6 and CXCR4 as major mediators of RTVP-1 effects on the mesenchymal transformation and self-renewal of GSCs. Using a pull down assay with His-tagged RTVP-1 and FRET analysis, we identified HSP27, N-WASP and hnRNPK as novel interacting proteins of RTVP-1, that mediate its effects on GSC migration and invadopodia formation. In summary, RTVP-1 expression is regulated by STAT3 and CEBPbeta and is promoting the mesenchymal transformation of GSCs. RTVP-1 induces self-renewal and migration of GSCs by the increased expression of IL-6 and CXCR4 and via its interaction with N-WASP, hnRNPK and HSP27. The upregulation of IL-6 by RTVP-1 acts in a positive feedback loop to further increase RTVP-1 expression by activating the STAT3 pathway. Collectively, these results implicate RTVP-1 as a novel prognostic marker and therapeutic target in GBM. |
