Expression of hepatocyte growth factor and c-met mRNAs during rat chemically induced hepatocarcinogenesis

• Published in: Carcinogenesis (New York) 1996-01, Vol.17 (1), p.19-24
• Main Authors: Imai, Toshio, Masui, Tsuneo, Nakanishi, Hayao, Inada, Ken-ichi, Kobayashi, Kiyoshi, Nakamura, Toshikazu, Tatematsu, Masae
• Format: Article
• Language: English
• Subjects: 2-Acetylaminofluorene; Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Diethylnitrosamine; Experimental digestive system and abdominal tumors; Glutathione Transferase - metabolism; Hepatectomy; Hepatocyte Growth Factor - genetics; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Male; Medical sciences; Precancerous Conditions - chemically induced; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Proto-Oncogene Proteins c-met; Rats; Rats, Inbred F344; Receptor Protein-Tyrosine Kinases - genetics; RNA, Messenger - analysis; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/17.1.19

The receptor for hepatocyte growth factor (HGF), a potent hepatocyte mitogen, is the product of the proto-oncogene 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, gluta-thione S-transferase placental form (GST-P)-positive pre-neoplastic 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.