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De-N-acetyl GM3 Promotes Melanoma Cell Migration and Invasion through Urokinase Plasminogen Activator Receptor Signaling–Dependent MMP-2 Activation

¹ Department of Oncology, the First Affiliated Hospital, and ² Departments of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, Liaoning, China; ³ Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and ⁴ Departments of Pathology, Microbiology and Immunology, Oncology Institute, Loyola University, Maywood, Illinois

Requests for reprints: Xiao-qi Wang, Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611. Phone: 312-503-0294; Fax: 312-503-0296; E-mail: x-wang1{at}northwestern.edu.

We have recently discovered that de-N-acetyl GM3 [NeuNH₂LacCer, d-GM3], a derivative of ganglioside GM3, is specifically expressed in metastatic tumor cells and that its expression correlates with an enhanced metastatic phenotype. Although the classic N-acetylated form of GM3 (NeuAcLacCer, c-GM3) is found in both normal and tumor cells, metastatic tumor cells (but not other cells) predominantly express d-GM3 (82–95% of total GM3). d-GM3 expression is mainly found in metastatic melanomas, but not in benign nevi or the majority of primary melanomas. Using metastatic (d-GM3–positive) and poorly invasive (d-GM3–negative) human melanoma cell lines, we found that d-GM3 stimulates cell migration and invasion by increasing the expression and activation of urokinase-like plasminogen activator (uPA). Further studies showed that d-GM3 activates matrix metalloproteinase-2 (MMP-2), but not MMP-9, when uPA receptor signaling is activated. These results implicate d-GM3 as a specific marker for metastatic melanoma and a novel therapeutic target for neoplastic diseases. [Cancer Res 2009;69(22):8662–9]

Key Words: ganglioside • uPA • uPAR • MMPs • metastatic marker