# HEPATOPOIETINS, LIVER REGENERATION AND CARCINOGENESIS

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 1992 · $217,319

## Abstract

Numerous past studies have shown that hepatocyte proliferation in liver
carcinogenesis and regeneration is regulated by specific growth factors and
their receptors.  Hepatocyte Growth Factor/Hepatopoietin A (HGF/HPTA) is a
large molecular weight heparin binding growth factor first identified by
the work funded by this grant.  The amino acid sequence of HGF/HPTA is now
known ( in part by work funded in the previous period of the grant) and the
cDNA for HGF/HPTA has been cloned and sequenced.  In the section on
Progress Report we present evidence that:

a. HGF/HPTA is most likely the factor which triggers liver regeneration.

b. HGF/HPTA increases in the plasma during liver enlargement caused by
hepatic tumor promoters.

c. Hepatocytes at late stages of hepatic tumor promotion cease responding
to HGF/HPTA.

d. HGF/HPTA is produced in many tissues (including brain ganglionic cells,
exocrine pancreas, gastrointestinal mucosa, but not in hepatocytes) and it
stimulates proliferation of many cell types that produce it.

e. Some hepatocellular carcinomas respond to HGF/HPTA.

f. Strong evidence was found to suggest that the receptor for HGF/HPTA is
the protooncogene c-MET.

In this application we propose to use already accumulated HGF/HPTA cDNA
probes and antisera against HGF/HPTA or fragment peptides in order to
further define the biological role of HGF/HPTA in liver regeneration and
carcinogenesis.  In addition to the above molecular tools, we will also use
cell culture and whole animal models, including initiation-promotion
protocols for liver carcinogenesis to carry out these studies.  Studies of
the second messenger system of HGF/HPTA will be conducted in a comparative
manner between normal and early neoplastic hepatocytes at different stages
of tumor promotion.  Detail analysis of its pathways of elimination in
normal animals and in rats exposed to liver tumor promoters will be carried
out, in order to determine the mechanisms by which HGF/HPTA increases in
hepatic tumor promotion.  Forced high expression of HGF/HPTA and its
effects on hepatocyte growth regulation and neoplastic initiation will be
carried out using transfection models in cell culture and transgenic mice
in which HGF/HPTA expression in hepatocytes is forced under the influence
of the metallothionin promoter.  The mechanisms leading to mito-inhibitory
effects of high levels of HGF/HPTA is several tumor cell lines and
hepatocytes will be further investigated.  The relationship between c-MET
proto-oncogene and HGF/HPTA receptor will be further explored and the role
of c-MET in liver carcinogenesis and regeneration will be further
investigated.  These studies focus exclusively on the effect of HGF/HPTA on
growth regulation of normal and neoplastic liver.  They will provide a
model, however, on which the complex already documented effects of HGF/HPTA
on other tissues can be better understood.

## Key facts

- **NIH application ID:** 3172971
- **Project number:** 2R01CA035373-10
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **SAM.gov UEI:** MKAGLD59JRL1
- **Principal Investigator:** GEORGE K MICHALOPOULOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $217,319
- **Award type:** 2
- **Project period:** 1983-07-15 → 1996-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172971

## Citation

> US National Institutes of Health, RePORTER application 3172971, HEPATOPOIETINS, LIVER REGENERATION AND CARCINOGENESIS (2R01CA035373-10). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172971. Licensed CC0.

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