Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development

During melanoma development, transformed cells evade keratinocyte-mediated control by downregulating cell adhesion molecules. This study investigated the regulation of cell adhesion by hepatocyte growth factor (HGF) in melano ma. Melanocytes and two melanoma lines, WM164 and WM35, expressed normal le vel E-cadherin and Desmoglein 1, whereas most melanomas (18 out of 20) expr essed no E-cadherin and significantly reduced Desmoglein 1. Overexpression of dominant negative E-cadherin and Desmoglein in melanocytes demonstrated that both molecules contribute to adhesion between melanocytes and keratino cytes. In contrast to melanocytes, most melanomas expressed HGF. All melano cytic cells expressed the HGF receptor c-Met, and autocrine HGF caused cons titutive activation of c-Met, MAPK and PI3K. When autocrine activation was induced with HGF-expressing adenovirus, E-cadherin and Desmoglein I were de creased in melanocytes, WM164 and WM35. MAPK inhibitor PD98059 and PI3K inh ibitor wortmannin partially blocked the downregulation, suggesting that bot h pathways are involved in this process. c-Met was coimmunoprecipitated wit h E-cadherin, Desmoglein I and Plakoglobin, suggesting that they form a com plex (es) that acts to regulate intercellular adhesion. Together, the resul ts indicate that autocrine HGF decouples melanomas from keratinocytes by do wnregulating E-cadherin and Desmoglein 1, therefore frees melanoma cells fr om the control by keratinocytes and allows dissemination of the tumor mass.