Hepatocyte growth factor/scatter factor and hepatocytes are potent downregulators of tyrosinase expression in B16 melanoma cells.
Reiterated selection in vivo of B16 murine melanoma cells for enhanced liver metastatic ability yielded a cel line (B16-LS9) dramatically overexpressing a constitutively active hepatocyte growth factor/scatter factor (HGF/SF) receptor, the product of the c-met proto-oncogene. Most likely because of their overexpressing c-met, B16-LS9 cells appear to be more responsive than parental B16-F1 cells to HGF stimulation, in terms of motility, invasion, and growth. They are also more pigmented, and express higher levels of tyrosinase as compared to parental B1 6-F1 cells. Therefore, we set out to explore whether HGF/SF and the liver might influence the differentiation state of B1 6 cells. We found that HGF/SF and MSH, two factors which reportedly have a strong influence on the phenotype and the malignant behavior of melanoma cells, may act at different levels, and with opposite results, on the regulation of gene expression. In fact, while MSH induces, at the transcriptional level, an increase in the production of both c-met and tyrosinase, HGF/SF, in contrast, promotes a decrease in the expression of both c-met and tyrosinase, however at a posttranscriptional level. These two opposite effects can counter-balance each other, when the cells are treated with both factors at the same time, apparently through a mechanism involving MAP kinase activation. The effects were, however, additive when morphological changes were considered. Most intriguingly, we also describe a very strong downregulatory activity, limited to tyrosinase expression, by hepatocytes in coculture with B16 cells. This activity, also at the posttranscriptional level, is much stronger than that exerted by HGF/SF, and appears to be due to a labile soluble factor produced by the hepatocytes.
Rusciano
D
D
Friedrich Miescher Institute, Basel, Switzerland. rusciano@fmi.ch
Lorenzoni
P
P
Lin
S
S
Burger
M M
MM
D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D009074:Melanocyte-Stimulating Hormones / Q000502:physiology; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000473:pathology; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D017228:Hepatocyte Growth Factor; D009074:Melanocyte-Stimulating Hormones; D014442:Monophenol Monooxygenase