| Resumo: | The SRY (sex-determining region Y) - box 2 (SOX2) is a master factor in the maintenance of pluripotency and stemness. The transcription factor SOX2 allows the cells to maintain the unique characteristics of the embryonic stem cells (ESCs), such as clonogenicity, pluripotency, self-renewal ability, and conservation of the anti-apoptotic properties of cancer stem cells (CSCs). This factor has an important role in carcinogenesis of several tumors, including gastric, breast, pancreatic, and lung cancers. SOX2 overexpression can contribute to resistance of cancer cell to drug therapy and has been associated with tumor aggressiveness and worse prognosis. Ras GTPase is a proto-oncogene activated in several types of cancer with low success rate, including carcinomas of the pancreas, colon, lung, thyroid, and myeloid malignancies. This oncogene activates several signalling pathways, which includes the MAPK, PI3K, and RAL. It’s signalling is involved in many cellular functions, such as cell proliferation, apoptosis, migration, fate specification, and differentiation. This project aims to investigate the role of SOX2 on RasV12-mediated transformation and the genetic requirements for SOX2 induction mediated by Ras using immortalized mouse fibroblasts and primary mouse embryonic fibroblasts. We also study the effect of SOX2 overexpression on drug therapy using human lung carcinoma and human breast adenocarcinoma cell lines. We have demonstrated that RasV12 overexpression induced the expression of SOX2 and this induction is at level of transcription. We also determined that p53, Rb, and p19ARF factors are not essential for SOX2 induction and that MAPK pathway is required, but not sufficient for SOX2 induction by RasV12. Through a transformation assay we demonstrate that SOX2 overexpression increases the effect of RasV12 in cell transformation and SOX2 silencing mediated by siRNA decreases the transformation capacities of RasV12, so this factor is important in transformation mediated by RasV12. Several studies show that SOX2 not only influences tumor growth, but it also influences the response of tumor cells to therapeutic drugs. We observed that SOX2 overexpression increased the resistance of human breast adenocarcinoma cells to docetaxel. In conclusion, SOX2 is a key factor in cell transformation mediated by RasV12, as well as has an important role in chemoresistance of cancer cells. Looking at these results, this factor can be a novel target for anti-cancer therapy.
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