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Osteonectin/SPARC Induction by Ectopic ß₃ Integrin in Human Radial Growth Phase Primary Melanoma Cells¹

The Wistar Institute, Philadelphia, Pennsylvania 19104 [R. A. S., K. S., B. V., M. H.]; Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia [R. A. S., B. B. G., D. J. S.]; and Department of Dermatology, University of Tübingen, Tübingen, Germany 72076 [F. M.]

Expression of the ß₃ integrin subunit in melanoma in situ has been found to correlate with tumor thickness, the ability to invade and metastasize, and poor prognosis. Transition from the radial growth phase (RGP) to the vertical growth phase (VGP) is a critical step in melanoma progression and survival and is distinguished by the expression of ß₃ integrin. The molecular pathways that operate in melanoma cells associated with invasion and metastasis were examined by ectopic induction of the ß₃ integrin subunit in RGP SBcl2 and WM1552C melanoma cells, which converts these cells to a VGP phenotype. We used cDNA representational difference analysis subtractive hybridization between ß₃-positive and -negative melanoma cells to assess gene expression profile changes accompanying RGP to VGP transition. Fourteen fragments from known genes including osteonectin (also known as SPARC and BM-40) were identified after three rounds of representational difference analysis. Induction of osteonectin was confirmed by Northern and Western blot analysis and immunohistochemistry and correlated in organotypic cultures with the ß₃-induced progression from RGP to VGP melanoma. Expression of osteonectin was also associated with reduced adhesion to vitronectin, but not to fibronectin. Osteonectin expression was not blocked when melanoma cells were cultured with anti-_vß₃ LM609 mAb, mitogen-activated protein kinase, or protein kinase C inhibitors, indicating that other signaling pathway(s) operate through _vß₃ integrin during conversion from RGP to VGP.

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