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Decreased hepatocyte growth factor level by Wy-14,643, non-genotoxic hepatocarcinogen in F-344 rats
1Department of Clinical Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
Abstract:
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.
Insights
Hepatocarcinogenesis induced by Wy-14,643 is linked to reduced hepatocyte growth factor (HGF). Lower HGF levels in Wy-14,643-treated rats correlated with tumor promotion, while HGF inhibited preneoplastic cell growth.
Area of Science:
- Hepatology
- Toxicology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a significant global health concern.
- Peroxisome proliferators, such as Wy-14,643, are known to induce liver tumors in rodents.
- The precise molecular mechanisms underlying Wy-14,643-induced hepatocarcinogenesis require further elucidation.
Purpose of the Study:
- To investigate the role of hepatocyte growth factor (HGF) in Wy-14,643-induced hepatocarcinogenesis.
- To determine the effect of Wy-14,643 on HGF expression and its potential impact on tumor promotion.
Main Methods:
- Male F-344 rats were administered Wy-14,643 orally or in diet for up to 78 weeks.
- Hepatic HGF mRNA levels were quantified using RT-PCR at various time points.
- Hepatic and plasma HGF protein levels were measured by ELISA.
- Colony formation assays were performed using preneoplastic/neoplastic liver cells in the presence of HGF.
Main Results:
- Wy-14,643 treatment led to a time-dependent and significant reduction in hepatic HGF mRNA and protein levels.
- Tumor portions of the liver showed greater HGF mRNA reduction compared to normal portions.
- HGF administration inhibited the colony formation of preneoplastic and neoplastic cells in a dose-dependent manner.
- HGF mRNA levels were also slightly reduced in the lung and kidney.
Conclusions:
- Reduced hepatic HGF levels induced by Wy-14,643 may play a crucial role in promoting neoplastic and preneoplastic cell growth.
- HGF exhibits an inhibitory effect on the proliferation of preneoplastic/neoplastic liver cells.
- These findings suggest a protective role for HGF against Wy-14,643-induced hepatocarcinogenesis.