Expression of the hepatocyte growth factor and c‐ MET genes during furan‐induced regenerative cell proliferation in the livers of B6C3F 1 mice and F‐344 rats

. Chronic administration of furan has been reported to produce hepatocellular carcinomas in male and female mice and male rats and cholangiocarcinomas in male and female rats. The weight of evidence indicates that furan is not genotoxic and tumours appear to arise secondary to initiation and promotional events associated with furan‐induced necrosis and regenerative cell proliferation. Identification of altered patterns of gene expression related to these events may provide insight into some of the underlying factors involved in this carcinogenic process. Hepatocyte growth factor (HGF) and its receptor, the protein product of the c‐met oncogene, play an important role in regenerative growth of liver. These experiments examined the relationship between induced cell proliferation and expression of the HGF and c ‐met genes in liver after treatment with furan. Male rats were administered a single necrosis‐inducing dose of furan, and male mice and male and female rats were treated daily with furan by gavage for up to six weeks under conditions of the cancer bioassay. Northern blot analysis of mRNA isolated from livers of those rats administered a single dose of furan detected a transient increase in expression in the HGF gene associated with the resulting wave of regenerative cell proliferation, but no increase in the expression of c‐met . No increase in expression of either gene was detected in liver tissue from any of the animals treated for up to six weeks, even though elevated rates of regenerative hepatocyte proliferation were sustained. Thus, given the detection limits of the techniques used here, sustained increases in expression of these genes are not required to maintain the regenerative response.