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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124414-03
Application #
7619540
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Forry, Suzanne L
Project Start
2007-07-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
3
Fiscal Year
2009
Total Cost
$249,536
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nejak-Bowen, Kari; Kikuchi, Alexander; Monga, Satdarshan P S (2013) Beta-catenin-NF-?B interactions in murine hepatocytes: a complex to die for. Hepatology 57:763-74
Delgado, Evan; Bahal, Raman; Yang, Jing et al. (2013) ?-Catenin knockdown in liver tumor cells by a cell permeable gamma guanidine-based peptide nucleic acid. Curr Cancer Drug Targets 13:867-78
Shin, Donghun; Monga, Satdarshan Pal Singh (2013) Cellular and molecular basis of liver development. Compr Physiol 3:799-815
Wickline, Emily Diane; Du, Yu; Stolz, Donna B et al. (2013) ?-Catenin at adherens junctions: mechanism and biologic implications in hepatocellular cancer after ?-catenin knockdown. Neoplasia 15:421-34
Lade, Abigale; Ranganathan, Sarangarajan; Luo, Jianhua et al. (2012) Calpain induces N-terminal truncation of ?-catenin in normal murine liver development: diagnostic implications in hepatoblastomas. J Biol Chem 287:22789-98
Awuah, Prince Kwaku; Rhieu, Byung Han; Singh, Sucha et al. (2012) ?-Catenin loss in hepatocytes promotes hepatocellular cancer after diethylnitrosamine and phenobarbital administration to mice. PLoS One 7:e39771
Awuah, Prince K; Monga, Satdarshan P (2012) Cell cycle-related kinase links androgen receptor and ?-catenin signaling in hepatocellular carcinoma: why are men at a loss? Hepatology 55:970-3
Bhat, Uppoor G; Jagadeeswaran, Ramasamy; Halasi, Marianna et al. (2011) Nucleophosmin interacts with FOXM1 and modulates the level and localization of FOXM1 in human cancer cells. J Biol Chem 286:41425-33
Wickline, Emily Diane; Awuah, Prince Kwaku; Behari, Jaideep et al. (2011) Hepatocyte ?-catenin compensates for conditionally deleted ?-catenin at adherens junctions. J Hepatol 55:1256-62
Thompson, Michael D; Dar, Mohd Jamal; Monga, Satdarshan P S (2011) Pegylated interferon alpha targets Wnt signaling by inducing nuclear export of ?-catenin. J Hepatol 54:506-12

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