GROWTH CONTROL OF NORMAL AND CIRRHOTIC HEPATOCYTES

Summary

Principal Investigator: Kevin Behrns
Abstract: Hepatocytes are unique parenchymal cells that divide and regenerate the liver in response to major injury. This regenerative capacity, however, leads to disordered hepatocyte growth in the chronically injured, cirrhotic liver. Hepatocytes in the cirrhotic liver respond differently to growth control signals. Most hepatocellular carcinomas arise in a cirrhotic liver, providing evidence that cirrhotic hepatocytes have altered growth control behavior. Cirrhosis is a major worldwide health problem that is expected to increase in prevalence because of increasing alcohol abuse and dissemination of the hepatitis B and C viruses, all major causes of cirrhosis. In an earlier proposal (K08), we hypothesized that cirrhotic hepatocytes would be less sensitive to apoptosis. Indeed, studies confirmed that cirrhotic hepatocytes are less responsive to multiple apoptotic agents including tumor necrosis factor a (TNFalpha), transforming growth factor beta (TGFbeta), and ultraviolet-C irradiation (UV-C). The resistance to TGFbeta-induced apoptosis is of special interest because this cytokine is a known inhibitor of hepatocyte growth, and it is present in high concentrations in the cirrhotic liver. The mechanisms by which TGFR induces hepatocyte apoptosis are not well known, but our studies in primary normal mouse hepatocytes suggest that this occurs through a caspase-8 dependent mechanism that requires the generation of reactive oxygen species, depolarization of the mitochondria with cytochrome c release, and caspase-3 activation. This is the first demonstration of caspase-8 dependence. The mechanisms that inhibit this pathway in cirrhotic hepatocytes are unknown, but may involve other TGFR-activated pathways such as the Smad signaling pathway. We hypothesize that the Smad signaling pathway is necessary for hepatocyte apoptosis, and that defects in this pathway are present in cirrhotic hepatocytes. Alterations in the Smad signaling pathway may alter pro- or anti-apoptotic factors that govern the cellular balance between survival and death. In this proposal, we aim to determine if the Smad signal transduction pathway is necessary for TGFbeta-induced hepatocyte apoptosis. In addition, because cirrhotic hepatocytes exhibit resistance to apoptosis that may be due to changes in expression of pro-and anti-apoptotic factors, we hypothesize that normal and cirrhotic hepatocytes differ in their gene expression profiles. We propose to identify and characterize differences in gene expression profiles between normal and cirrhotic hepatocytes in response to apoptotic stimuli. Examination of these hypotheses will allow our laboratory to growth both in depth and in breadth, because we will use new microarray technology provided within the UNC Genomics Core and Microarray Facility. We will continue to seek counsel from our K08 mentors (Drs. David Brenner and Lola Reid) and use liberally the UNC Center for Gastrointestinal Biology and Disease for core facilities such as the Molecular Imaging Core.
Funding Period: 2002-09-01 - 2005-05-31
more information: NIH RePORT

Top Publications

  1. pmc Ski promotes tumor growth through abrogation of transforming growth factor-beta signaling in pancreatic cancer
    T Ryan Heider
    Department of Surgery, Division of Gastrointestinal Surgery, University of North Carolina, Chapel Hill, NC, USA
    Ann Surg 246:61-8. 2007
  2. pmc Transforming growth factor beta mediates hepatocyte apoptosis through Smad3 generation of reactive oxygen species
    Dalliah Black
    Department of Surgery, 4024 Burnett Womack Building, CB 7050, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    Biochimie 89:1464-73. 2007

Detail Information

Publications2

  1. pmc Ski promotes tumor growth through abrogation of transforming growth factor-beta signaling in pancreatic cancer
    T Ryan Heider
    Department of Surgery, Division of Gastrointestinal Surgery, University of North Carolina, Chapel Hill, NC, USA
    Ann Surg 246:61-8. 2007
    ..We hypothesized that human pancreatic cancer resists TGF-beta signaling and cell death through increased Ski expression...
  2. pmc Transforming growth factor beta mediates hepatocyte apoptosis through Smad3 generation of reactive oxygen species
    Dalliah Black
    Department of Surgery, 4024 Burnett Womack Building, CB 7050, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    Biochimie 89:1464-73. 2007
    ..In conclusion, TGFbeta-induced hepatocyte apoptosis occurs through Smad3 dependent activation of ROS with subsequent activation of the MPT and caspases...