Intronic miR-211 assumes the tumor suppressive function of its host gene in melanoma.
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.
Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
Carmit
C
Levy
Mehdi
M
Khaled
Dimitrios
D
Iliopoulos
Maja M
MM
Janas
Steffen
S
Schubert
Sophie
S
Pinner
Po-Hao
PH
Chen
Shuqiang
S
Li
Anne L
AL
Fletcher
Satoru
S
Yokoyama
Kenneth L
KL
Scott
Levi A
LA
Garraway
Jun S
JS
Song
Scott R
SR
Granter
Shannon J
SJ
Turley
David E
DE
Fisher
Carl D
CD
Novina
D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007438:Introns / Q000235:genetics*; D008545:Melanoma / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics*
C549405:MIRN211 microRNA, human; D035683:MicroRNAs; D050778:NFATC Transcription Factors; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II