Csig-28. novel function of brachyury as a potent regulator of hedgehog signaling and stemness in glioma

Glioblastomas (GB) are the aggressive primary brain tumors with a survival of only ~1.5 years from initial diagnosis. Resistance to conventional therapies and tumor recurrence in GB has been attributed to the presence of glioma stem cells (GSCs), a subpopulation of cells which exhibit self-renewal and tumorigenesis. Brachyury, an evolutionarily conserved member of T-box family transcription factors, has been implicated in pathobiology of chordomas, lung cancer and hepatocellular carcinoma in adults; it regulates epithelial-mesenchymal transition and chemoresistance in cancer cells. However, the potential role of Brachyury in the progression of GB tumors is still unknown. We identified a significant overexpression of Brachyury protein in GSC neurospheres compared with attached glioma cell lines; conversely, serum-induced differentiation of GSCs resulted in loss of Brachyury expression accompanied by decreased levels of stemness markers. To further investigate the functional relevance of Brachyury in GSCs and glioma cells, we conducted loss-and gain-of function studies using shRNA and full-length overexpression plasmids, respectively. Brachyury knockdown in GSCs led to sphere dissociation and a significant loss of stemness markers including CD133, Nanog and Nestin; of note, Brachyury knockdown also inhibited sonic hedgehog (Shh) signaling and reduced Gli1 levels in these cells. On the other hand, overexpression of Brachyury elevated Shh/Gli1 signaling and increased stem ce...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: CELL SIGNALING AND SIGNALING PATHWAYS Source Type: research