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The Promyelocytic Leukemia Zinc Finger–MicroRNA-221/-222 Pathway Controls Melanoma Progression through Multiple Oncogenic Mechanisms

¹ Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore Sanità and ² Department of Histopathology, II Faculty of Medicine and Surgery, Sant' Andrea Hospital, University "La Sapienza," Rome, Italy, and ³ Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Fondazione Istituti Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy

Requests for reprints: Alessandra Carè, Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore Sanità, Viale Regina Elena, 299-00161 Rome, Italy. Phone: 39-06-49902411; Fax: 39-06-49387087; E-mail: alessandra.care{at}iss.it.

Key Words: microRNA • PLZF • melanoma • tumor progression • antagomir

The incidence of cutaneous melanoma is steadily increasing. Although several molecular abnormalities have been associated with melanoma progression, the mechanisms underlying the differential gene expression are still largely unknown and targeted therapies are not yet available. Noncoding small RNAs, termed microRNAs (miR), have been recently reported to play important roles in major cellular processes, including those involved in cancer development and progression. We have identified the promyelocytic leukemia zinc finger (PLZF) transcription factor as a repressor of miR-221 and miR-222 by direct binding to their putative regulatory region. Specifically, PLZF silencing in melanomas unblocks miR-221 and miR-222, which in turn controls the progression of the neoplasia through down-modulation of p27Kip1/CDKN1B and c-KIT receptor, leading to enhanced proliferation and differentiation blockade of the melanoma cells, respectively. In vitro and in vivo functional studies, including the use of antisense "antagomir" oligonucleotides, confirmed the key role of miR-221/-222 in regulating the progression of human melanoma; this suggests that targeted therapies suppressing miR-221/-222 may prove beneficial in advanced melanoma. [Cancer Res 2008;68(8):2745–10]

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