# HEPADNAVIRUS ASSOCIATED HEPATOCELLULAR CARCINOMA

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 1992 · $359,226

## Abstract

The overall goal of this proposal is to understand the molecular basis of
hepatocellular carcinoma in hepadnavirus carriers.  The first two specific
aims of the proposal will involve and in-depth study of a new system we
have developed to study the role of topoisomerase activity in viral
replication and integration.  Specific Aim 1 will focus on the mechanism by
which Camptothecin (CPT), a specific Topoisomerase I inhibitor, inhibits
viral replication in cytoplasmic capsids in a chicken hepatoma cell line
(LMH) transfected with a mutant (IS) DHBV genome which accumulates
cytoplasmic capsid particles and recycles DHBV DNA into the nucleus.  In
addition to time course and dose response experiments, site specific
mutagenesis of DHBV DNA and immune precipitation experiments will establish
the nature of the topoisomerase activity and provide new genetic mapping
information of the DHBV Pol gene.  We will also express the spacer domain
of the DHBV Pol gene and test it for topoisomerase activity "in vitro."
Specific Aim 2 will study the effect of CPT on the transport of DHBV DNA to
the nucleus and its processing in the nucleus.  We will determine whether
CPT treatment induces integrated molecules using an integration assay based
on inverse PCR technology.  The studies in Specific Aim 3 will focus on
gene expression in precancerous nodules of the woodchuck.  We will attempt
to understand the mechanism of N-myc activation in precancerous nodules.
By studying the activity of a group of selected genes by "in situ"
hybridization we will gain insight into molecular mechanisms associated
with precancerous lesions.  In conjunction with this, we will utilize two
woodchuck liver epithelial cell lines to directly test the effects of IL1,
IL6, and TNF-alpha on N-myc expression.  Specific Aim 4 will directly test
the effect of IGF-II in hepatocarcinogenesis using transgenic mouse mating
experiments.  Using the first transgenic mouse line to produce IGF-II in
the adult mouse liver (developed by us) we will determine if IGF-II
functions synergistically with HBV envelope proteins in inducing HCC.  In
a reverse approach, we will also test whether knocking out the endogeneous
IGF-II gene prevents or inhibits the HBsAg lesion from progressing to HCC.
Finally, we will utilize our transgenic mouse models (HBsAg line 50-4, and
SV40 T Ag) to determine whether the maternally imprinted IGF-II allele can
be activated during hepatocarcinogenesis.  This experiment will increase
our general understanding of a possible tumor suppressor, or cancer
protective, role of gene imprinting.

## Key facts

- **NIH application ID:** 3175036
- **Project number:** 2R01CA037232-09
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Charles E. Rogler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $359,226
- **Award type:** 2
- **Project period:** 1984-04-01 → 1996-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3175036

## Citation

> US National Institutes of Health, RePORTER application 3175036, HEPADNAVIRUS ASSOCIATED HEPATOCELLULAR CARCINOMA (2R01CA037232-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3175036. Licensed CC0.

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