This research focuses on studies of viral and cellular pathogenesis of human hepatocellular carcinoma (HCC) one of the most common and devastating malignant tumors in the world. During the previous grant period, we have shown that generation of hepatitis B virus (HBV) variants occurs during active replication and these molecular events may lead to viral persistence in the liver. We now wish to define their role in the development of HCC and 1) assess the biological properties of HBV variants, determine if HBV variant forms integrate into tumor DNA and investigate the cellular proteins which interact with the viral HBx transactivator and may be important in the regulation of growth control genes in the liver. In addition, previous investigations by us have demonstrated that the insulin receptor substrate-1 protein (IRS-1), a substrate for tyrosine kinase containing growth factor receptors, is overexpressed in HBV related human HCC. Furthermore, preliminary studies presented herein suggest that simple three to four fold overexpression of IRS-1 leads to cellular transformation and activates the growth factor mediated signal transduction cascade. In this regard we will 2) determine if IRS-1 and another protein namely p36 protein kinase substrate are overexpressed in HCC tumors derived from man and various experimental animal models and represent general features of mammalian hepatocyte transformation. The concentration of these molecules in early preneoplastic lesions in the liver will also be assessed during the natural history of tumor development. At the molecular level, other experiments will evaluate functional domains of the IRS-1 molecule and determine if expression of IRS-1 and mutant constructs with Y to F changes in tile YVNI and YMXM motifs that alter the binding of GRB2 and PtdIns-3- kinase proteins respectively, leads to malignant transformation through activation of the various known cellular pathways associated with the growth factor mediated signal transduction cascade. In addition, the functional significance of the Syp binding site for a tyrosine phosphatase and the pleckstrin homology (PH) G-beta-gamma binding domain of IRS-1 protein will be explored since little is known regarding their role in cellular transformation. Finally, we have shown that the 5' upstream regulatory region of the IRS-1 gene contains AP-1 and AP-2 transcription factor binding sites. Growth control genes with such regulatory regions have been found to be upregulated by the HBx transactivator protein. Thus, we plan studies to possibly link viral and cellular factors and 3) determine if the HBx transactivator protein, along with its recently identified cellular partners, upregulate IRS-1 gene expression. These efforts will provide new information on the viral and cellular mechanisms of hepatocarcinogenesis and the role of overexpression of genes such as IRS-1 and p36 during this process.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA035711-16
Application #
6051126
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1983-07-01
Project End
2000-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
16
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Rhode Island Hospital (Providence, RI)
Department
Type
DUNS #
161202122
City
Providence
State
RI
Country
United States
Zip Code
02903
Tsedensodnom, Orkhontuya; Koga, Hironori; Rosenberg, Stephen A et al. (2011) Identification of T-cell factor-4 isoforms that contribute to the malignant phenotype of hepatocellular carcinoma cells. Exp Cell Res 317:920-31
von dem Bussche, Annette; Machida, Raiki; Li, Ke et al. (2010) Hepatitis C virus NS2 protein triggers endoplasmic reticulum stress and suppresses its own viral replication. J Hepatol 53:797-804
Toyama, Takashi; Lee, Han Chu; Koga, Hironori et al. (2010) Noncanonical Wnt11 inhibits hepatocellular carcinoma cell proliferation and migration. Mol Cancer Res 8:254-65
Gehring, Stephan; Gregory, Stephen H; Wintermeyer, Philip et al. (2009) Generation of immune responses against hepatitis C virus by dendritic cells containing NS5 protein-coated microparticles. Clin Vaccine Immunol 16:163-71
Tsai, Adrienne; Kawai, Shigenobu; Kwei, Karen et al. (2009) Chimeric constructs between two hepatitis B virus genomes confirm transcriptional impact of core promoter mutations and reveal multiple effects of core gene mutations. Virology 387:364-72
Longato, Lisa; de la Monte, Suzanne; Kuzushita, Noriyoshi et al. (2009) Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology 49:1935-43
Laperle, Christopher M; Hamilton, Theron J; Wintermeyer, Philip et al. (2008) Low density contrast agents for x-ray phase contrast imaging: the use of ambient air for x-ray angiography of excised murine liver tissue. Phys Med Biol 53:6911-23
Kim, Eun; Li, Ke; Lieu, Charmiane et al. (2008) Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis. J Hepatol 49:787-98
Bengochea, A; de Souza, M M; Lefrancois, L et al. (2008) Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma. Br J Cancer 99:143-50
Gehring, Stephan; Gregory, Stephen H; Wintermeyer, Philip et al. (2008) Generation and characterization of an immunogenic dendritic cell population. J Immunol Methods 332:18-30

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