Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor

• DOI: 10.1073/pnas.0808263106
• Publication Date: 2009-02-03T02:35:01Z
• Authors: Miguel F. Segura; Douglas Hanniford; Silvia Menendez; Linsey Reavie; Xuanyi Zou; Silvia Alvarez-Diaz; Jan Zakrzewski; Elen Blochin; Amy Rose; Dusan Bogunovic; David Polsky; Jianjun Wei; Peng Lee; Ilana Belitskaya-...; Nina Bhardwaj; Iman Osman; Eva Hernando
• Keywords: 0301 basic medicine; Microphthalmia-Associated Transcription Factor; Cell Survival; Forkhead Box Protein O3; Forkhead Transcription Factors; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; MicroRNAs; 03 medical and health sciences; Cell Movement; Disease Progression; Tumor Cells, Cultured; Animals; Humans; Neoplasm Metastasis; Melanoma

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.