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Intronic miR-211 assumes the tumor suppressive function of its host gene in melanoma
Authors:Levy Carmit  Khaled Mehdi  Iliopoulos Dimitrios  Janas Maja M  Schubert Steffen  Pinner Sophie  Chen Po-Hao  Li Shuqiang  Fletcher Anne L  Yokoyama Satoru  Scott Kenneth L  Garraway Levi A  Song Jun S  Granter Scott R  Turley Shannon J  Fisher David E  Novina Carl D
Institution:Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
Abstract: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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