COEXPRESSION AND REGULATION OF MET AND RON PROTOONCOGENES IN HUMAN HEPATOCELLULAR-CARCINOMA TISSUES AND CELL-LINES

Met and von proto-oncogenes encode the cell surface receptors for hepa tocyte growth factor (HGF) and hepatocyte growth factor-like (HLP) pro tein, respectively, and induce mitogenesis, motogenesis, morphogenesis , and metastatic activity in various cell types. Overexpression of met in human carcinoma has been reported by several groups including ours ; however, the mechanisms that control met gene expression are thus fa r unclear, The present study focuses on the expression and regulation of the Met and Ron receptors in human hepatocellular carcinoma (HCC). We report here that abnormal expression of met and ron proteins occurs in some cases of human HCC. Using several HCC cell lines as a model s ystem, we show that HGF, as well as other cytokines, such as epidermal growth factor (EGF), interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha), induce met and ron expression . Using several chimeric constructs consisting of various lengths of t he met promoter region fused to the reporter gene of chloramphenicol a cetyl transferase (CAT), and by performing transient transfection of t hese constructs into HepG2 cells, we show that induction of met gene e xpression by HGF and other cytokines is, at least in part, through up- regulation of met gene promoter activity. The DNA region conferring re sponsiveness to cytokine induction was located within 0.2 kb of the me t core promoter, Interestingly, EGF did not stimulate met promoter act ivity in any of the met-CAT chimeric constructs. These results provide evidence that met and ron are modulated in the liver by a similar cyt okine network. In the case of met expression, the 0.2-kb region in the met gene promoter may play an important role in mediating its gene in duction in response to HGF and other cytokines. Our results also sugge st that unregulated expression of met and ron may be associated with p athological conditions, such as HCC, in the liver.