Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor.
The highly aggressive character of melanoma makes it an excellent model for probing the mechanisms underlying metastasis, which remains one of the most difficult challenges in treating cancer. We find that miR-182, member of a miRNA cluster in a chromosomal locus (7q31-34) frequently amplified in melanoma, is commonly up-regulated in human melanoma cell lines and tissue samples; this up-regulation correlates with gene copy number in a subset of melanoma cell lines. Moreover, miR-182 ectopic expression stimulates migration of melanoma cells in vitro and their metastatic potential in vivo, whereas miR-182 down-regulation impedes invasion and triggers apoptosis. We further show that miR-182 over-expression promotes migration and survival by directly repressing microphthalmia-associated transcription factor-M and FOXO3, whereas enhanced expression of either microphthalmia-associated transcription factor-M or FOXO3 blocks miR-182's proinvasive effects. In human tissues, expression of miR-182 increases with progression from primary to metastatic melanoma and inversely correlates with FOXO3 and microphthalmia-associated transcription factor levels. Our data provide a mechanism for invasion and survival in melanoma that could prove applicable to metastasis of other cancers and suggest that miRNA silencing may be a worthwhile therapeutic strategy.
Segura
Miguel F
MF
Department of Pathology, Interdisciplinary Melanoma Cooperative Group, New York University Medical Center. New York, NY 10016, USA.
Hanniford
Douglas
D
Menendez
Silvia
S
Reavie
Linsey
L
Zou
Xuanyi
X
Alvarez-Diaz
Silvia
S
Zakrzewski
Jan
J
Blochin
Elen
E
Rose
Amy
A
Bogunovic
Dusan
D
Polsky
David
D
Wei
Jianjun
J
Lee
Peng
P
Belitskaya-Levy
Ilana
I
Bhardwaj
Nina
N
Osman
Iman
I
Hernando
Eva
E
D000818:Animals; D002465:Cell Movement; D002470:Cell Survival; D018450:Disease Progression; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D014407:Tumor Cells, Cultured
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D035683:MicroRNAs; D051739:Microphthalmia-Associated Transcription Factor; C538984:Mirn182 microRNA, human