Journal
MOLECULAR CELL
Volume 40, Issue 5, Pages 841-849Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2010.11.020
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Funding
- National Institutes of Health (NIH) [AR043369]
- Melanoma Research Alliance
- Adelson Medical Research Foundation
- US-Israel Binational Science Foundation
- Doris Duke Medical Foundation
- American Cancer Society
- NRSA [NIH/NCI T32 CA070083]
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When it escapes early detection, malignant melanoma becomes a highly lethal and treatment-refractory cancer. Melastatin is greatly downregulated in metastatic melanomas and is widely believed to function as a melanoma tumor suppressor. Here we report that tumor suppressive activity is not mediated by melastatin but instead by a microRNA (miR-211) hosted within an intron of melastatin. Increasing expression of miR-211 but not melastatin reduced migration and invasion of malignant and highly invasive human melanomas characterized by low levels of melastatin and miR-211. An unbiased network analysis of melanoma-expressed genes filtered for their roles in metastasis identified three central node genes: IGF2R, TGFBR2, and NFAT5. Expression of these genes was reduced by miR-211, and knockdown of each gene phenocopied the effects of increased miR-211 on melanoma invasiveness. These data implicate miR-211 as a suppressor of melanoma invasion whose expression is silenced or selected against via suppression of the entire melastatin locus during human melanoma progression.
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