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Melanoma Proteoglycan Modifies Gene Expression to Stimulate Tumor Cell Motility, Growth, and Epithelial-to-Mesenchymal Transition

¹ Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; ² Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; ³ Section of Hematology/Oncology, Department of Medicine and University of Chicago Cancer Research Center, University of Chicago, Chicago, Illinois; ⁴ Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan, P.R. China; ⁵ Hillman Cancer Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; and ⁶ London Regional Cancer Center, University of Western Ontario, London, Ontario, Canada

Requests for reprints: James B. McCarthy, Department of Laboratory Medicine and Pathology, University of Minnesota, MMC 609, 420 Delaware Street Southeast, Minneapolis, MN 55455. Phone: 612-625-7454; Fax: 612-625-1121; E-mail: mccar001{at}umn.edu.

Key Words: c-Met • Erk1,2 activation • Melanoma proteoglycan

Melanoma chondroitin sulfate proteoglycan (MCSP) is a plasma membrane–associated proteoglycan that facilitates the growth, motility, and invasion of tumor cells. MCSP expression in melanoma cells enhances integrin function and constitutive activation of Erk1,2. The current studies were performed to determine the mechanism by which MCSP expression promotes tumor growth and motility. The results show that MCSP expression in radial growth phase, vertical growth phase, or metastatic cell lines causes sustained activation of Erk1,2, enhanced growth, and motility which all require the cytoplasmic domain of the MCSP core protein. MCSP expression in a radial growth phase cell line also promotes an epithelial-to-mesenchymal transition based on changes in cell morphology and the expression of several epithelial-to-mesenchymal transition markers. Finally, MCSP enhances the expression of c-Met and hepatocyte growth factor, and inhibiting c-Met expression or activation limits the increased growth and motility of multiple melanoma cell lines. The studies collectively show the importance of MCSP in promoting progression by an epigenetic mechanism and they indicate that MCSP could be targeted to delay or inhibit tumor progression in patients. [Cancer Res 2009;69(19):7538–47]