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.
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