Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Beta-catenin: A friend or foe in liver pathobiology?

Thompson, Michael David (2010) Beta-catenin: A friend or foe in liver pathobiology? Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (4MB) | Preview


Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide due to poor prognosis and limited therapeutic options. Point mutations affecting phosphorylation sites such as serine-45 in Beta-catenin gene are evident in around 30% of HCC. We developed a transgenic mouse that expresses Ser45 mutated Beta-catenin (TG) in hepatocytes. While this mutation did not induce spontaneous tumorigenesis, it promoted diethylnitrosamine (DEN)-induced HCC through cyclin-D1 overexpression and other factors.The Wnt/Beta-catenin signaling is important in stem cell self-renewal. The adult progenitor cell of the liver, or oval cells that emanate from atypical ductular proliferation (ADP), maybe involved in liver regeneration and/or hepatocarcinogenesis and can be observed after exposure to DDC diet, which induces hepatic and biliary injury. When challenged with chronic-DDC diet, Beta-catenin transgene led to a cellular disparity in the form of increased appearance of atypical hepatocytes (positive for ductular marker A6), which was associated with better resolution of intrahepatic cholestasis. We also utilized DDC diet in conditional Beta-catenin knockout mice (KO) that lacked Beta-catenin in hepatocytes and cholangiocytes. ADP was blunted after short-term DDC feeding in KO mice; however, long-term feeding resulted in gradual increase in ADP, hepatic fibrosis and HCC. Interestingly, the KO livers begin to exhibit periportal Beta-catenin-positive hepatocytes, which eventually populate the entire livers over the course of this process. Finally, we explored targeting of the Wnt pathway with pegylated interferon-alpha2A (Peg-IFN). We found that Peg-IFN decreased Beta-catenin activity in mouse liver and several human hepatoma cell lines. The mechanism seemed to be at least partly due to upregulation of a nuclear export factor, RanBP3.Thus, this study characterizes an animal model utilizing Beta-catenin mutation, which is evident in HCC patients. DEN-exposure in these animals led to HCC development, thus providing a valuable tool to study mechanisms of hepatocarcinogenesis and providing a model to test therapeutic inhibition of Beta-catenin by agents such as peg-IFN and others. Our studies also provide evidence that Wnt activation may resolve intrahepatic cholestasis. Finally, we show that chronic damage to the liver in KO led to appearance of Beta-catenin-positive hepatocytes, which continued to proliferate and in the face of continued injury and fibrosis, led to development of HCC, which is also relevant clinically.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Thompson, Michael Davidmit14@pitt.eduMIT14
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMichalopoulos, Georgemichalopoulosgk@upmc.eduMICHAL
Committee MemberBahary, Nathanbahary@pitt.eduBAHARY
Committee MemberMonga,
Committee MemberYin, Xiao-Mingxmyin@pitt.eduXMYIN
Committee MemberLiu, Youhualiuy@upmc.eduYHLIU
Date: 14 July 2010
Date Type: Completion
Defense Date: 25 May 2010
Approval Date: 14 July 2010
Submission Date: 4 June 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: fibrosis; liver stem cell; cancer therapy; liver cancer
Other ID:, etd-06042010-133720
Date Deposited: 10 Nov 2011 19:46
Last Modified: 19 Dec 2016 14:36


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item