ROLE OF HOST AND HBV GENES IN PRIMARY LIVER CANCER

Project: Research project

Project Details

Description

Hepatitis B virus (HBV) is an agent which infects man, integrates into the
genome of a specific tissue (liver), and probably causes hepatocellular
carcinoma (HCC). In the United States, there are over three quarters of a
million individuals with persistent HBV infection and worldwide HCC is one
of the leading causes of death from cancer. The purpose of this proposal
is to examine the specificities, location and effects of the integrated HBV
DNA sequences within the host genome; and, to examine host and other
factors regulating the response to HBV infection. Using recombinant DNA
and molecular hybridization technology, four specific questions will be
addressed. 1. Does the HBV genome insert within a certain region of the
host genome? 2. Since males are at a greater risk for persistent HBV
infection and the development of HCC, is the HBV genome susceptible to
hormonal regulation? 3. Does modification of DNA sequences, such as by
methylation, contribute to HBV and host DNA expression? 4. Are
transforming genes activated in HBV-associatd HCC? The methodology used to
investigate these questions will include: construction of recombinant DNA
molecules containing integrated HBV seuqences from DNA of HCC tumors
containing only one site of integrated HBV DNA; isolation and
characterization of host flanking sequences with use of a single copy
sequence probe to map the sites of integration to a specific chromosome in
a human X rodent somatic cell hybrid panel; in vitro effects of androgens
and corticosteroids on cultured hepatoma cells containing HBV DNA with
examination of transcription and protein production; determination of
methylation in DNA obtained from HCC cells and HBV-infected hepatocytes by
paired restriction digestion with methyl sensitive and insensitive enzymes
followed by Southern blot analysis; and, transfection of HCC DNA into
untransformed cells by Ca phosphate precipitation with subsequent assay for
transformed phenotype in recipient cells. The long-term objectives of this
proposal are to understand the molecular features of a naturally occurring
disease in man whereby new genes are introduced and expressed in a tissue
specific manner. This biologic process is central to elucidation of the
mechanism involved in carcinogenesis. Furthermore, dissection of the host
factors involved in persistent HBV infection should allow the development
of new therapies.
StatusFinished
Effective start/end date1/1/901/1/90

Funding

  • National Cancer Institute

ASJC

  • Genetics
  • Molecular Biology
  • Oncology
  • Cancer Research

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