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Osteonectin downregulates E‐cadherin, induces Osteopontin and Focal adhesion kinase activity stimulating an invasive melanoma phenotype
Author(s) -
Smit Darren J.,
Gardiner Brooke B.,
Sturm Richard A.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23039
Subject(s) - osteonectin , osteopontin , downregulation and upregulation , cancer research , cadherin , focal adhesion , epithelial–mesenchymal transition , melanoma , cell migration , cell adhesion , tumor progression , phosphorylation , biology , chemistry , microbiology and biotechnology , medicine , cell , immunology , cancer , gene , biochemistry , alkaline phosphatase , osteocalcin , enzyme
Osteonectin is recognised as a marker of metastasis progression in melanoma and has been implicated in the transition from radial to vertical growth phase. A Tetracycline‐inducible system was used to regulate Osteonectin protein levels in melanoma cell lines to examine the morphological, biochemical and invasive changes that accompany its altered expression. Assay of protein and phosphorylation changes showed a downregulation of E‐cadherin, upregulation of Osteopontin and a corresponding increase in phosphorylation of Focal Adhesion Kinase on Tyr 397 and Tyr 576 concomitant with Osteonectin induction. Melanoma cells overexpressing Osteonectin displayed increased invasive potential, whereas ablation of Osteonectin gene transcription using siRNA suppressed the invasive potential of these cells and resulted in the upregulation of E‐cadherin. The recently described interaction of Osteonectin with Integrin Linked Kinase leading to modulation of its activity suggests a mechanism relevant to the loss of E‐cadherin and cell adhesion that occurs during melanoma progression. These results indicate a central role for Osteonectin in the regulation of gene expression changes driving the progression of melanoma toward metastasis. © 2007 Wiley‐Liss, Inc.