ADAM10 is upregulated in melanoma metastasis compared with primary melanoma.
ADAM10 (a disintegrin and metalloproteinase 10) is involved in the ectodomain shedding of various substrates, including adhesion molecules such as L1 cell adhesion molecule (L1-CAM) and CD44, which are known to have important roles in the development of malignant melanoma. In our study, we characterized the expression of ADAM10 in melanoma cells in vitro and in vivo. Immunohistochemical analysis on tissue microarrays indicated that ADAM10 expression was significantly elevated in melanoma metastasis compared with primary melanomas. In vitro downregulation of ADAM10 with specific small interfering RNA (siRNA) resulted in a suppression of the anchorage-independent cell growth and reduced the migration of melanoma cells. In addition, overexpression of ADAM10 induced the migration of melanoma cells. In cell lines from melanoma patients with metastasis, ADAM10 was significantly overexpressed, and ADAM10 expression correlated with increased cell proliferation. Furthermore, we present evidence that ADAM10 is involved in the release of L1-CAM from melanoma cells. It is important that knockdown of cellular L1-CAM reduced the migration of melanoma cells and abrogated the chemoresistance against cisplatin. In contrast, soluble L1-CAM had no effect on melanoma cell migration or cell survival. Taken together, our data demonstrate that ADAM10 and L1-CAM have important roles during melanoma progression and both molecules represent attractive targets for therapeutical intervention of melanomas.
Pharmazentrum frankfurt/ZAFES, Department of Pharmacology, University Hospital Goethe, University of Frankfurt, Frankfurt am Main, Germany.
Sophia B
SB
Lee
Anja
A
Schramme
Kai
K
Doberstein
Reinhard
R
Dummer
Mohamed S
MS
Abdel-Bakky
Sascha
S
Keller
Peter
P
Altevogt
Shin T
ST
Oh
Jörg
J
Reichrath
Daniel
D
Oxmann
Josef
J
Pfeilschifter
Daniela
D
Mihic-Probst
Paul
P
Gutwein
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000503:physiopathology* / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism; D009508:Nevus, Pigmented / Q000473:pathology / Q000503:physiopathology; D034741:RNA, Small Interfering; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000502:physiology
D000970:Antineoplastic Agents; D008565:Membrane Proteins; D039842:Neural Cell Adhesion Molecule L1; D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D002945:Cisplatin