OVERVIEW: The overall goals of the research program have been to understand the molecular-genetic basis for hepatocarcinogenesis in hepadnavirus carrier. Hepadnaviral DNA integrations are agents of genetic change which can promote the process of hepatocarcinogenesis. Our recent data have established several features of the integration process. First, single and multiple integrations occur continuously through successive cell generations. Second, the integration frequency can vary dramatically in subclones of the same cell line. Third, integrations can be amplified and can also be lost from successive generations of cells. Fourth, the loss of an integration can be accompanied by the loss of cellular DNA associated with the integration. These results provide the basis for integrations to function as activators of protooncogenes, as well as agents of the loss of tumor suppressor genes during hepatocarcinogenesis.
The specific aims of the current proposal will study the mechanisms responsible for the processes described above.
SPECIFIC AIM 1 : Studies on the molecular mechanisms associated with the acquisition and loss of DHBV integrations in LMH-D2 chicken hepatoma cells.
SPECIFIC AIM 2 : Studies on the effects of DHBV mutations which alter the structure of viral DNA's, or the amplification of nuclear CCC DHBV DNA's, on integrations in clonal populations of cells.
SPECIFIC AIM 3 : Studies on the effects of genotoxic agents, likely to be encountered during persistent infection, on the net accumulation or loss of DHBV integrations in LMH cells.
SPECIFIC AIM 4 : Studies on the acquisition, loss, or rearrangement of DHBV integrations during the growth of hepatomas in immunocompromized hosts.
SPECIFIC AIM 5 : Reconstitution of nu/nuupa mouse liver with woodchuck hepatocytes. Recent advances in the use of transgenic mice and hepatocyte transplantation now make it feasible for us to attempt to produce an animal model in which we will be able to clonally amplify and isolate woodchuck hepatocytes from all stages of carcinogenic progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037232-15
Application #
2700359
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Cole, John S
Project Start
1984-04-01
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Rogler, Charles E; Bebawee, Remon; Matarlo, Joe et al. (2017) Triple Staining Including FOXA2 Identifies Stem Cell Lineages Undergoing Hepatic and Biliary Differentiation in Cirrhotic Human Liver. J Histochem Cytochem 65:33-46
Rogler, Leslie E; Kosmyna, Brian; Moskowitz, David et al. (2014) Small RNAs derived from lncRNA RNase MRP have gene-silencing activity relevant to human cartilage-hair hypoplasia. Hum Mol Genet 23:368-82
Connolly, Erin C; Van Doorslaer, Koenraad; Rogler, Leslie E et al. (2010) Overexpression of miR-21 promotes an in vitro metastatic phenotype by targeting the tumor suppressor RHOB. Mol Cancer Res 8:691-700
Rogler, Charles E; Levoci, Lauretta; Ader, Tammy et al. (2009) MicroRNA-23b cluster microRNAs regulate transforming growth factor-beta/bone morphogenetic protein signaling and liver stem cell differentiation by targeting Smads. Hepatology 50:575-84
Connolly, Erin; Melegari, Margherita; Landgraf, Pablo et al. (2008) Elevated expression of the miR-17-92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype. Am J Pathol 173:856-64
Rogler, Charles E; Zhou, Hong Chou; LeVoci, Lauretta et al. (2007) Clonal, cultured, murine fetal liver hepatoblasts maintain liver specification in chimeric mice. Hepatology 46:1971-8
Hajjou, Mustapha; Norel, Raquel; Carver, Robert et al. (2005) cDNA microarray analysis of HBV transgenic mouse liver identifies genes in lipid biosynthetic and growth control pathways affected by HBV. J Med Virol 77:57-65
Rogler, Charles E; Tchaikovskaya, Tatyana; Norel, Raquel et al. (2004) RNA expression microarrays (REMs), a high-throughput method to measure differences in gene expression in diverse biological samples. Nucleic Acids Res 32:e120
Plescia, C; Rogler, C; Rogler, L (2001) Genomic expression analysis implicates Wnt signaling pathway and extracellular matrix alterations in hepatic specification and differentiation of murine hepatic stem cells. Differentiation 68:254-69
Pourquier, P; Jensen, A D; Gong, S S et al. (1999) Human DNA topoisomerase I-mediated cleavage and recombination of duck hepatitis B virus DNA in vitro. Nucleic Acids Res 27:1919-25

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