AP2[alpha] controls the dynamic balance between miR-126&126 and miR-221&222 during melanoma progression

• Published in: Oncogene Vol. 35; no. 23; p. 3016
• Main Authors: Felli, N, Errico, M C, Pedini, F, Petrini, M, Puglisi, R, Bellenghi, M, Boe, A, Felicetti, F, Mattia, G, De Feo, A, Bottero, L, Tripodo, C, Carè, A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 09.06.2016
• Subjects: Leukemia; Melanoma; Metastasis; MicroRNAs
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.357

Accumulating evidences have shown the association between aberrantly expressed microRNAs (miRs) and cancer, where these small regulatory RNAs appear to dictate the cell fate by regulating all the main biological processes. We demonstrated the responsibility of the circuitry connecting the oncomiR-221&222 with the tumor suppressors miR-126&126* in melanoma development and progression. According to the inverse correlation between endogenous miR-221&222 and miR-126&126*, respectively increasing or decreasing with malignancy, their enforced expression or silencing was sufcient for a reciprocal regulation. In line with the opposite roles of these miRs, protein analyses conrmed the reverse expression pattern of miR-126&126*-targeted genes that were induced by miR-221&222. Looking for a central player in this complex network, we revealed the dual regulation of AP2, on one side directly targeted by miR-221&222 and on the other a transcriptional activator of miR-126&126*. We showed the chance of restoring miR-126&126* expression in metastatic melanoma to reduce the amount of mature intracellular heparin-binding EGF like growth factor, thus preventing promyelocytic leukemia zinc nger delocalization and maintaining its repression on miR-221&222 promoter. Thus, the low-residual quantity of these two miRs assures the release of AP2 expression, which in turn binds to and induces miR-126&126* transcription. All together these results point to an unbalanced ratio functional to melanoma malignancy between these two couples of miRs. During progression this balance gradually moves from miR-126&126* toward miR-221&222.