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A greater understanding of the molecular events that initiate and promote HCC development will aid in the development of new therapeutic strategies. STAT3 is constitutively activated in HCC and is important for maintaining tumor survival. We propose to delineate the critical steps in signal transduction by which tyrosine-phosphorylated STAT3 is activated in HCC cells. We found that oncogenic Ras inhibits the expression of SHP2, which is necessary for the dephosphorylation of STAT3. Further studies have shown that the Ras-mediated inhibition of SHP2 expression is associated with increased levels of expression and phosphorylation of the transcription factor E2F1. We have also observed that activated E2F1 is a prerequisite for the activation of STAT3 and STAT3-dependent transcription in HCC cells. In this proposal, we will determine whether oncogenic Ras inhibits SHP2 expression through increased expression and/or activity of E2F1. 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