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Publications

Journal Article Research Support, Non-U.S. Gov't Epublish 4 citations

PubMed: 38472212 DOI: 10.1038/s41419-024-06580-2

The MITF/mir-579-3p regulatory axis dictates BRAF-mutated melanoma cell fate in response to MAPK inhibitors.

Cell Death Dis 15(3):208

Authors: Domenico Liguoro, Rachele Frigerio, Arianna Ortolano, Andrea Sacconi, Mario Acunzo, Giulia Romano, Giovanni Nigita, Barbara Bellei, Gabriele Madonna, Mariaelena Capone, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto, Luigi Fattore

Affiliations

  • SAFU Laboratory, Department of Research, Advanced Diagnostics and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
  • Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, 88100, Catanzaro, Italy.
  • Department of Anatomy, Histology, Forensic- Medicine and Orthopedics, Sapienza University of Rome, 00161, Rome, Italy.
  • Clinical Trial Center, Biostatistics and Bioinformatics Unit, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
  • Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
  • Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
  • Laboratory of Cutaneous Physiopathology, San Gallicano Dermatological Institute, IRCCS, 00144, Rome, Italy.
  • Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131, Naples, Italy.
  • Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy.
  • Faculty of Medicine and Psychology, Department Clinical and Molecular Medicine, Sant'Andrea Hospital-Sapienza University of Rome, 00118, Rome, Italy.
  • Scientific Directorate, IRCSS Regina Elena National Cancer Institute, 00144, Rome, Italy.

Abstract

Therapy of melanoma has improved dramatically over the last years thanks to the development of targeted therapies (MAPKi) and immunotherapies. However, drug resistance continues to limit the efficacy of these therapies. Our research group has provided robust evidence as to the involvement of a set of microRNAs in the development of resistance to target therapy in BRAF-mutated melanomas. Among them, a pivotal role is played by the oncosuppressor miR-579-3p. Here we show that miR-579-3p and the microphthalmia-associated transcription factor (MITF) influence reciprocally their expression through positive feedback regulatory loops. In particular we show that miR-579-3p is specifically deregulated in BRAF-mutant melanomas and that its expression levels mirror those of MITF. Luciferase and ChIP studies show that MITF is a positive regulator of miR-579-3p, which is located in the intron 11 of the human gene ZFR (Zink-finger recombinase) and is co-transcribed with its host gene. Moreover, miR-579-3p, by targeting BRAF, is able to stabilize MITF protein thus inducing its own transcription. From biological points of view, early exposure to MAPKi or, alternatively miR-579-3p transfection, induce block of proliferation and trigger senescence programs in BRAF-mutant melanoma cells. Finally, the long-term development of resistance to MAPKi is able to select cells characterized by the loss of both miR-579-3p and MITF and the same down-regulation is also present in patients relapsing after treatments. Altogether these findings suggest that miR-579-3p/MITF interplay potentially governs the balance between proliferation, senescence and resistance to therapies in BRAF-mutant melanomas.

MeSH

Melanoma, Cells, Therapeutics, Cell Death, Genes, Microphthalmia-Associated Transcription Factor, Down-Regulation

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