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

Gang Li, Helmut Schaider, Kapaettu Satyamoorthy, Yasushi Hanakawa, Koji Hashimoto, Meenhard Herlyn

    Research output: Contribution to journalArticle

    156 Citations (Scopus)

    Abstract

    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 melanoma. Melanocytes and two melanoma lines, WM164 and WM35, expressed normal level E-cadherin and Desmoglein 1, whereas most melanomas (18 out of 20) expressed 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 keratinocytes. In contrast to melanocytes, most melanomas expressed HGF. All melanocytic cells expressed the HGF receptor c-Met, and autocrine HGF caused constitutive activation of c-Met, MAPK and PI3K. When autocrine activation was induced with HGF-expressing adenovirus, E-cadherin and Desmoglein 1 were decreased in melanocytes, WM164 and WM35. MAPK inhibitor PD98059 and PI3K inhibitor wortmannin partially blocked the downregulation, suggesting that both pathways are involved in this process, c-Met was coimmunoprecipitated with E-cadherin, Desmoglein 1 and Plakoglobin, suggesting that they form a complex (es) that acts to regulate intercellular adhesion. Together, the results indicate that autocrine HGF decouples melanomas from keratinocytes by downregulating E-cadherin and Desmoglein 1, therefore frees melanoma cells from the control by keratinocytes and allows dissemination of the tumor mass.

    Original languageEnglish
    Pages (from-to)8125-8135
    Number of pages11
    JournalOncogene
    Volume20
    Issue number56
    DOIs
    Publication statusPublished - 2001

    Fingerprint

    Desmoglein 1
    Hepatocyte Growth Factor
    Cadherins
    Melanoma
    Down-Regulation
    Melanocytes
    Keratinocytes
    Phosphatidylinositol 3-Kinases
    Desmogleins
    gamma Catenin
    Proto-Oncogene Proteins c-met
    Cell Adhesion Molecules
    Adenoviridae
    Cell Adhesion

    All Science Journal Classification (ASJC) codes

    • Molecular Biology
    • Genetics
    • Cancer Research

    Cite this

    Li, Gang ; Schaider, Helmut ; Satyamoorthy, Kapaettu ; Hanakawa, Yasushi ; Hashimoto, Koji ; Herlyn, Meenhard. / Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. In: Oncogene. 2001 ; Vol. 20, No. 56. pp. 8125-8135.
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    Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. / Li, Gang; Schaider, Helmut; Satyamoorthy, Kapaettu; Hanakawa, Yasushi; Hashimoto, Koji; Herlyn, Meenhard.

    In: Oncogene, Vol. 20, No. 56, 2001, p. 8125-8135.

    Research output: Contribution to journalArticle

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    AU - Hashimoto, Koji

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