The receptor for hepatocyte growth factor (HGF), a potent hepatocyte mitogen, is the product of the protooncogene c-met. In order to cast light on their significance for hepatocarcinogenesis, levels of both HGF and c-met mRNA were evaluated in rat livers during development of 2-acetylaminofluorene (2-AAF)-selected preneoplastic nodules and carcinomas following diethylnitrosamine (DEN) initiation. Rats were given a single i.p. injection of 200 mg/kg body wt DEN and, starting 2 weeks later, were administered 0.015% 2-AAF in the diet for up to 6 weeks. All rats were subjected to partial hepatectomy (PH) at week 3. Additional animals undergoing the DEN, 2-AAF and PH regimen were sacrificed at week 40 to allow evaluation of carcinomas. Oval cell proliferation, glutathione S-transferase placental form (GST-P)-positive preneoplastic lesion development and HGF and c-met mRNA levels were sequentially analyzed after PH. Numerous oval cells were observed 1 week after PH, but were remarkably reduced 2 weeks thereafter. The areas of GST-P-positive foci and nodules rapidly increased with time not only during 2-AAF feeding, but also to the same degree for at least 2 weeks after cessation of carcinogenic insult. Dot blot analysis showed HGF transcripts to be elevated after PH and during the selective growth conditions of 2-AAF feeding, dropping after cessation of carcinogenic insult. In the c-met transcript case transient increases were observed after PH, followed by a decrease, c-met over-expression in nodular livers did not correlate with the presence of 2-AAF or lesion development. In most hepatocellular carcinoma samples expression of both HGF and c-met mRNAs was below levels in non-neoplastic regions. These data suggest that HGF and c-met are directly involved in a paracrine growth pathway controlling proliferation in normal hepatocytes and oval cells, but not in preneoplastic and neoplastic cells.
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