MicroRNA-dependent regulation of cKit in cutaneous melanoma.
Loss of cKit receptor in cutaneous melanomas was attributed to the down-regulation of AP2 transcription factor. Our analysis of 27 melanoma cell lines showed no correlation between AP2 and c-kit expression. Suggesting a post-transcriptional mechanism of cKit down-modulation, we performed genome-wide microRNA (miRNA) expression profiling and found that several miRNA species are commonly up-regulated in melanomas. Among them was mir-221, which can directly interact with c-kit 3'UTR and inhibit cKit protein translation. Observed inverse correlation of the c-kit and mir-221 expression in various melanocytic cells pointed to its involvement in regulation of cKit in melanoma. Moreover, a series of functional assays demonstrated that mir-221 could directly inhibit cKit, p27(Kip1) and, possibly, other pivotal proteins in melanoma. Collectively, the studies presented here indicate that mir-221 could be a novel therapeutic target for the treatment of cutaneous melanoma. They also suggest that regulation of expression and functional activity of identified up-regulated miRNAs should be further studied in the context of malignant melanoma.
Igoucheva
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Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, 233 S. 10th Street, Philadelphia, PA 19107, USA.
Alexeev
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D020413:3' Untranslated Regions / Q000378:metabolism; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D035683:MicroRNAs / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D050656:Transcription Factor AP-2 / Q000096:biosynthesis
D020413:3' Untranslated Regions; D050760:Cyclin-Dependent Kinase Inhibitor p27; D035683:MicroRNAs; D019009:Proto-Oncogene Proteins c-kit; D050656:Transcription Factor AP-2; C525709:MIR221, human