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Carcinogenesis, Vol 18, 1303-1309, Copyright © 1997 by Oxford University Press

ARTICLES

Decreased hepatocyte growth factor level by Wy-14,643, non-genotoxic hepatocarcinogen in F-344 rats

Y Motoki, H Tamura, R Morita, T Watanabe and T Suga
Department of Clinical Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.

We examined the role of hepatocyte growth factor (HGF) in the hepatocarcinogenesis caused by [4-chloro-6-(2,3-xylidino)-2- pyrimidinylthio] acetic acid (Wy-14,643), a peroxisome proliferator. Wy- 14,643 (100 mg/kg body wt or 0.1% (w/w) in diet) was given orally to male F-344 rats for up to 78 weeks. At 78 weeks the hepatocarcinomas or adenomas in the livers of Wy-14,643-treated rats were observed. Markedly decreased amounts of hepatic HGF mRNA were observed in rats fed Wy-14,643 for 78 weeks. The degree of reduction was higher in the tumour portions of the liver than in the normal portions. After 7 days of treatment with Wy-14,643 (100 mg/kg body wt), the expression of hepatic HGF mRNA was slightly decreased. Wy-14,643 treatment resulted in a time-dependent decrease in hepatic HGF mRNA levels to 63% of the control level after 14 days of treatment. In long-term treatment (18-40 weeks), hepatic HGF mRNA levels were reduced further, reaching 44% of the control level at the 40-week stage. As shown by ELISA, the amounts of hepatic and plasma HGF were significantly decreased by 60 and 50%, respectively, compared with controls. The degree of the reduction correlated with the level of hepatic HGF mRNA. In the lung and kidney, also HGF secretory organs, Wy-14,643 slightly reduced the amount of HGF mRNA. In the colony assay using preneoplastic or neoplastic cells from Wy-14,643-treated livers, 5-15 ng/ml of HGF, which induces proliferation in normal hepatocytes, inhibited the colony formation of neoplastic or preneoplastic cells. The inhibitory effect was dependent on HGF concentration. In the presence of 300 ng/ml HGF, the growth of colonies was suppressed to 36% of the control level. These findings indicate that reductions in hepatic HGF levels, induced by Wy-14,643, may play an important role in the promotion of neoplastic or preneoplastic cell growth.
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Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation
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