Ras regulation of gene expression in ovarian carcinogenesis.

摘要

The role of aberrant Ras activation in human carcinogenesis and cancer progression has been well-established. Although our understanding of the mechanisms of Ras-induced signal transduction is now considerable, recent studies have revealed a greater complexity to the mechanisms of Ras-induced transformation. Activated Ras mediates its biological effects through activation of multiple effector signaling cascades that regulate transcription factor activation and alter the expression of specific genes. However, effector utilization may be cell-type as well as species-specific and may vary based on the particular aspect of Ras transformation that is examined. Thus, the broad goal of my research has been to determine the contribution of three key Ras effectors to Ras-mediated transformation and gene deregulation in ovarian epithelial cells.; My studies have established that activation of the Raf/MEK/ERK pathway is necessary for and contributes significantly to morphologic and growth transformation of rat ovarian surface epithelial (ROSE) cells. These findings contrast with those in other human and rodent epithelial cell types, where Raf activation alone was not sufficient for transformation. Although oncogenic Ras does not activate the phosphatidylinositol 3-kinase (PI3K) effector pathway, basal levels of PI3K activity may play a role in some, but not all, aspects of Ras-mediated ROSE cell transformation. We also determined that aberrant Ras upregulation of matrix metal lop roteinase-3 (MMP-3) and MMP-10 gene and protein expression, but not cathepsin L expression and secretion, was mediated solely by Raf/MEK/ERK activation and is not necessary for morphologic or growth transformation. In contrast, downregulation of transforming growth factor-beta receptor II (TGFβRII) gene and protein expression required both Raf-dependent and -independent pathway activation. Furthermore, we found that TGFβRII downregulation contributed to growth, but not morphologic, transformation in ROSE cells. Taken together, these studies suggest that the Raf effector pathway may play a significant role in ovarian epithelial cancer, mediating the deregulation of two classes of genes that have been implicated in tumor progression and contribute to distinct aspects of oncogenic Ras transformation. The recent identification of B-Raf mutations in 30% of human ovarian serous carcinomas is consistent with our conclusion.