Regulation of HGF and HGFR gene expression.

Hepatocyte growth factor and its receptor (the product of the c-met protooncogene) are believed to be necessary for the normal growth and development of many tissues and organs. This ligand/receptor system controls essential cellular responses such as cell proliferation and motility as well as morphogenesis and differentiation. HGF mRNA is expressed primarily in mesenchymal but not in epithelial cells while its receptor is predominately expressed in epithelial cells. This pattern of HGF and HGFR gene expression in combination with the unique biological effects of HGF on its target cells has led to the postulate that HGF is one of the long-sought mediators conveying cross-talk between the epithelial and stromal compartments of a given tissue. The expression of HGF and HGFR genes are unregulated in several types of human cancer; therefore, understanding the control mechanisms governing HGF and HGFR gene expression is of great clinical interest. Toward this goal, we have analyzed the effects of various physiological agents such as cytokines and hormones on the expression of HGF and the HGFR in a multitude of cell types in vitro. Moreover, we have cloned and analyzed the HGF promoter and its 5'-flanking region to uncover the basis for its inducible and cell-type specific expression at the transcriptional level. Our results indicate that HGF and HGFR gene expression is inducible and their expression is orchestrated in stromal and epithelial cells, respectively, by extracellular signals derived from steroid hormones as well as cytokines such as IL-1, IL-6, and TNF alpha.