mda-9/Syntenin: a positive regulator of melanoma metastasis.
Metastasis is a significant event in cancer progression and continues to pose the greatest challenge for a cancer cure. Defining genes that control metastasis in vivo may provide new targets for intervening in this process with profound therapeutic implications. Melanoma differentiation associated gene-9 (mda-9) was initially identified by subtraction hybridization as a novel gene displaying biphasic expression during terminal differentiation in human melanoma cells. Mda-9, also known as syntenin, is a PDZ-domain protein overexpressed in many types of human cancers, where it is believed to function in tumor progression. However, a functional role of mda-9/syntenin in tumor growth and metastasis and the signaling pathways involved in mediating these biological activities remain to be defined. Evidence is now provided, using weakly and highly metastatic isogenic melanoma variants, that mda-9/syntenin regulates metastasis. Expression of mda-9/syntenin correlates with advanced stages of melanoma progression. Regulating mda-9/syntenin expression using a replication-incompetent adenovirus expressing either sense or antisense mda-9/syntenin modifies the transformed phenotype and alters metastatic ability in immortal human melanocytes and metastatic melanoma cells in vitro and in vivo in newborn rats. A direct relationship is observed between mda-9/syntenin expression and increased phosphorylation of focal adhesion kinase, c-Jun-NH2-kinase, and p38. This study provides the first direct link between mda-9/syntenin expression and tumor cell dissemination in vivo and indicates that mda-9/syntenin expression activates specific signal transduction pathways, which may regulate melanoma tumor progression. Based on its ability to directly alter metastasis, mda-9/syntenin provides a promising new focus for melanoma cancer research with potential therapeutic applications for metastatic diseases.
Boukerche
Habib
H
Department of Pathology, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York 10032, USA.
Su
Zao-Zhong
ZZ
Emdad
Luni
L
Baril
Patrick
P
Balme
Brigitte
B
Thomas
Luc
L
Randolph
Aaron
A
Valerie
Kristoffer
K
Sarkar
Devanand
D
Fisher
Paul B
PB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism / Q000502:physiology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D051381:Rats; D017208:Rats, Wistar; D053676:Syntenins; D014161:Transduction, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C109621:SDCBP protein, human; D053676:Syntenins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases