Research Papers:
Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells
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Abstract
Marianna Vitiello1,2, Andrea Tuccoli1, Romina D’Aurizio3, Samanta Sarti1,4, Laura Giannecchini1, Simone Lubrano1,4, Andrea Marranci1,4, Monica Evangelista2, Silvia Peppicelli5, Chiara Ippolito6, Ivana Barravecchia7, Elena Guzzolino7, Valentina Montagnani8, Michael Gowen9, Elisa Mercoledi1, Alberto Mercatanti2, Laura Comelli2, Salvatore Gurrieri1, Lawrence W. Wu10, Omotayo Ope10, Keith Flaherty11, Genevieve M. Boland11, Marc R. Hammond11, Lawrence Kwong12, Mario Chiariello2,13, Barbara Stecca8, Gao Zhang10, Alessandra Salvetti14, Debora Angeloni7, Letizia Pitto2, Lido Calorini5, Giovanna Chiorino15, Marco Pellegrini3, Meenhard Herlyn10, Iman Osman9, Laura Poliseno1,2
1Oncogenomics Unit, Core Research Laboratory, Istituto Toscano Tumori (ITT), AOUP, Pisa, Italy
2Institute of Clinical Physiology (IFC), CNR, Pisa, Italy
3Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics (IIT), CNR, Pisa, Italy
4University of Siena, Italy
5Section of Experimental Pathology and Oncology, Department of Experimental and Clinical Biomedical Sciences, University of Firenze, Italy
6Unit of Histology, Department of Clinical and Experimental Medicine, University of Pisa, Italy
7Scuola Superiore Sant’Anna, Pisa, Italy
8Tumor Cell Biology Unit, Core Research Laboratory, Istituto Toscano Tumori (ITT), AOUC, Firenze, Italy
9New York University, New York, NY, USA
10The Wistar Institute, Philadelphia, PA, USA
11Massachusetts General Hospital, Boston, MA, USA
12MD Anderson Cancer Center, Houston, TX, USA
13Signal Transduction Unit, Core Research Laboratory, Istituto Toscano Tumori (ITT), AOUS, Siena, Italy
14Unit of Experimental Biology and Genetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy
15Fondazione Edo and Elvo Tempia, Biella, Italy
Correspondence to:
Laura Poliseno, email: [email protected]
Keywords: melanoma, BRAFV600E, ERK pathway, miR-204 family, context-dependency
Received: March 11, 2016 Accepted: February 06, 2017 Published: March 06, 2017
ABSTRACT
Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that BRAFV600E regulates through the ERK pathway.
By performing small RNA sequencing on A375 melanoma cells and a vemurafenib-resistant clone that was taken as negative control, we discover miR-204 and miR-211 as the miRNAs most induced by vemurafenib. We also demonstrate that, although belonging to the same family, these two miRNAs have distinctive features. miR-204 is under the control of STAT3 and its expression is induced in amelanotic melanoma cells, where it acts as an effector of vemurafenib’s anti-motility activity by targeting AP1S2. Conversely, miR-211, a known transcriptional target of MITF, is induced in melanotic melanoma cells, where it targets EDEM1 and consequently impairs the degradation of TYROSINASE (TYR) through the ER-associated degradation (ERAD) pathway. In doing so, miR-211 serves as an effector of vemurafenib’s pro-pigmentation activity. We also show that such an increase in pigmentation in turn represents an adaptive response that needs to be overcome using appropriate inhibitors in order to increase the efficacy of vemurafenib.
In summary, we unveil the distinct and context-dependent activities exerted by miR-204 family members in melanoma cells. Our work challenges the widely accepted “same miRNA family = same function” rule and provides a rationale for a novel treatment strategy for melanotic melanomas that is based on the combination of ERK pathway inhibitors with pigmentation inhibitors.
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