Significant similarities exist in the mechanisms of development & cancer. Wnt/beta-Catenin & HGF/Met signaling pathways have been shown to play an important role in embryogenesis and carcinogenesis. We have previously demonstrated significance of beta-catenin in regulated liver growth during regeneration following two-third partial hepatectomy & in embryonic liver cultures. Aberrations in this pathway resulting in stabilization & redistribution of beta- catenin protein, due to mutations in beta-catenin, axin, GSKbeta & other unidentified reasons, have been demonstrated in unregulated liver growth in hepatocellular cancers & hepatoblastomas. We have also reported a cross talk between the Wnt & HGF pathways in liver owing to a novel association between beta-catenin & Met, a tyrosine kinase HGF receptor. HGF induced tyrosine phosphorylation dependent nuclear translocation of beta-catenin by triggering the dissociation of Met-beta-catenin complex at the hepatocyte membrane. Our hypothesis is that understandinq the regulation of these 2 pathways in liver development & reqeneration will be imperative to comprehend their roles in liver cancer with possible proqnostic, diaqnostic or therapeutic implications. We plan to examine these pathways using several existing models. An ontogenic analysis of beta-catenin & antisense studies in ex vivo embryonic liver cultures has revealed its important role during early liver development. This analysis has also demonstrated a tight temporal regulation of beta-catenin during liver development & it is lost in the liver after E16 stage. We will examine Met-beta-catenin & tyrosine phosphorylation dependent regulation of beta-catenin during liver development, regeneration & in primary hepatocyte cultures (with & without matrigel). Secondly, we have generated transgenic mice overexpressing non-mutant beta-catenin in liver, utilizing an albumin promoter. Characterization of these animals will enable us to examine the impact of beta-catenin deregulation on proliferation, apoptosis, stem cell compartment & lineage specification during liver development. These animals will be also utilized to perform partial hepatectomy studies to examine the effect of elevated beta-catenin protein on liver growth. Microarray analysis on transgenic livers will be useful to determine liver-specific target genes of this pathway. Thirdly, we have acquired beta-catenin floxed & albumin-cre mice that are now being used to generate beta-catenin conditional knockout mice. These will be characterized for understanding the in vivo role of beta-catenin in liver development by a thorough analysis. The ex vivo culture system will utilize livers from such mice for further characterization, analysis & intervention. Thus this study will be a comprehensive analysis of Wnt/beta-catenin pathway and its interactions with HGF in liver development & growth.
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