Detection of the c-met proto-oncogene product in normal skin and tumours of melanocytic origin

The proto-oncogene c-met product (c-MET) is a receptor tyrosine kinase and functions as a receptor for hepatocyte growth factor (HGF). Although the function of c-MET has yet to be fully clarified, HGF stimulates the phosphorylation of tyrosyl residues on c-MET and triggers the signal transduction pathways, resulting in a contribution to the malignant progression of melanonocytes with synergic factors such as basic fibroblast growth factor and mast cell growth factor. Using immunohistochemical methods, we have studied the localization of c-MET in normal skin and various melanocytic tumours, c-MET was detected in keratinocytes, melanocytes, sebaceous cells, and other cells of the skin. In particular, basal melanocytes almost always showed nuclear labelling. Melanocytic naevi generally revealed predominantly nuclear staining of cells in the epidermis, whereas only a few cases showed a distinct cytoplasmic localization of c-MET in dermal naevus cells. The distribution pattern of c-MET in melanoma cells was basically similar to that of benign lesions, although the numbers tested were small. Cultured human melanoma cells also showed predominantly nuclear labelling, but were unresponsive to exogenous c-MET ligand HGF. Treatment with the glucosidase inhibitor castanospermine caused accumulation of protein at 220 kD, without diminishing the amount of normally-processed 190-kD c-MET. Although there was no significant difference in c-MET distribution between benign and malignant melanocytic lesions, it is suggested that malignant transformation of melanocytes may be associated with loss of response to HGF or other growth-regulating factors.