De-N-acetyl GM3 promotes melanoma cell migration and invasion through urokinase plasminogen activator receptor signaling-dependent MMP-2 activation.
We have recently discovered that de-N-acetyl GM3 [NeuNH(2)LacCer, 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.
Liu
Ji-Wei
JW
Department of Oncology, the First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China.
Sun
Ping
P
Yan
Qiu
Q
Paller
Amy S
AS
Gerami
Pedram
P
Ho
Nancy
N
Vashi
Neelam
N
Le Poole
I Caroline
IC
Wang
Xiao-qi
XQ
D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005679:G(M3) Ganglioside / Q000031:analogs & derivatives / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014162:Transfection
D014408:Biomarkers, Tumor; D005679:G(M3) Ganglioside; D055293:Receptors, Urokinase Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9