Role of the neural-stem cell transcription factor Sox2 in the proliferation of glioblastoma cells (2014)

Undergraduates: Anna Sirbu, Ralf Schmid

Faculty Advisor: Ryan Miller
Department: Biology

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The transcription factor Sox2 plays a key role in neural development where its expression is necessary in neural stem cells for maintaining pluripotency. Sox2 expression has also been associated with various cancers, including glioblastoma (GBM), the most aggressive and common form of primary brain cancer that remains incurable. The underlying mechanism of GBM origination and proliferation are poorly understood, and the function of Sox2 still remains unknown.
The consequences of Sox2 depletion were investigated in glioblastoma stem cell (GSC) lines derived from genetically engineered mice that contain genetic alterations most commonly found in human GBM. Sox2 knockdown was achieved through activation of a shRNA hairpin directed against Sox2 and led to more than 70% depletion of Sox2 protein in all cell lines, although the functional outcome differed. Cells with disrupted control over the G1/S cell cycle checkpoint entered into cell cycle arrest and stopped proliferating. Additional constitutive activation of the Ras-MAPK pathway did not overcome cell growth inhibition. However, the additional deletion of the tumor suppressor PTEN resulted in insensitivity to Sox2 deletion. These results suggest that GSC with the complex genetic lesions, as found in GBM, can evade the downregulation of Sox2 and maintain characteristics of neural stem cells. Future research will determine how these GSC maintain stem cell characteristics in absence of the essential transcription factor Sox2.