Aberrant activation of ?-Catenin occurs in many cancers including HCC. Although the activation of ?-catenin in HCC has been shown to be multifactorial, all events converge at ?-catenin, making it an attractive therapeutic target in HCC. We have shown pro-proliferative effect of ?-catenin in liver in transgenic mice, liver regeneration, liver development &in hepatocyte cultures. To more efficiently elucidate its role in hepatic biology, we have generated conditional ?-catenin knockout mice using the cre- lox system. ?-Catenin floxed mice (Ex2-6) were bred to Albumin-Cre or a-fetoprotein-albumin-Cre mice to generate ?-catenin conditional null mice: Ctnnb1 loxP/loxp:Alb-Cre OR Ctnnb1 loxP/loxp:aFP-Alb-Cre respectively. Both these mice are born normally &show about 95% loss of ?-catenin by 2 weeks that persists throughout their normal life span in the former, while 100% loss of ?-catenin occurs in the latter by 4-5 months and succumb due to diminished liver size &function. In addition, we have recently characterized the normal ?-catenin over-expressing transgenic (TG) mice under albumin promoter/enhancer. These mice have a higher basal hepatocyte proliferation, with ensuing hepatomegaly. More recently we have generated TG mice that over expresses stable form of ?-catenin (Ser45 mutated). These mice are being characterized, and demonstrate a more robust phenotype than normal ?-catenin TG mice. These models give us a unique opportunity to conclusively address the role of ?-catenin in HCC induction and progression. We propose to employ the DEN/phenobarbital model to investigate hepatocarcinogenesis in absence of ?-catenin or presence of stable ?-catenin. In addition, we propose to investigate oval cell activation, a preneoplastic event in liver, in knockout and transgenic mice to assertively address role of ?-catenin in this event. Lastly, we would explore the role of therapeutic inhibition of ?-catenin in transgenic models. We have identified role of R-Etodolac (enantiomer of NSAID Etolodolac, lacking cox-2 inhibition) in inhibiting ?-catenin in hepatoma cells. This drug is in phase-ll clinical trials in refractory CLL. We propose to examine the effect of R-Etodolac in our transgenic mice and in tumor xenograft models in a series of both in vitro and in vivo studies to ascertain its role as an anti- ?-catenin for treatment or chemoprophylaxis in HCC. Thus this proposal will lay the ground work for initiating clinical studies directed against ?-catenin in HCC.
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