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Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b

2015; Impact Journals LLC; Volume: 7; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.6599

1949-2553

Elisabetta Vergani, Lorenza Di Guardo, Matteo Dugo, Sara Rigoletto, Gabrina Tragni, Roberta Ruggeri, Federica Perrone, Elena Tamborini, Annunziata Gloghini, Flavio Arienti, Barbara Vergani, Paola Deho, Loris De Cecco, Viviana Vallacchi, Paola Frati, Eriomina Shahaj, Antonello Villa, Mario Santinami, Filippo de Braud, Licia Rivoltini, Monica Rodolfo,

Cancer Mechanisms and Therapy

// Elisabetta Vergani 1, * , Lorenza Di Guardo 2, * , Matteo Dugo 3, * , Sara Rigoletto 1 , Gabrina Tragni 4 , Roberta Ruggeri 5 , Federica Perrone 4 , Elena Tamborini 4 , Annunziata Gloghini 4 , Flavio Arienti 6 , Barbara Vergani 7 , Paola Deho 1 , Loris De Cecco 3 , Viviana Vallacchi 1 , Paola Frati 1 , Eriomina Shahaj 1 , Antonello Villa 7 , Mario Santinami 5 , Filippo De Braud 2 , Licia Rivoltini 1 , Monica Rodolfo 1 1 Immunotherapy Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 3 Functional Genomics and Bioinformatics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 4 Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 5 Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 6 Immunohematology and Transfusion Medicine Service, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 7 Consorzio MIA, Microscopy and Image Analysis, University of Milan Bicocca, Monza, Italy * These authors have contributed equally to this work Correspondence to: Monica Rodolfo, e-mail: monica.rodolfo@istitutotumori.mi.it Keywords: melanoma, BRAF inhibitor, CCL2, drug resistance, miRNAs Received: June 22, 2015 Accepted: November 25, 2015 Published: December 14, 2015 ABSTRACT In melanoma, the adaptative cell response to BRAF inhibitors includes altered patterns of cytokine production contributing to tumor progression and drug resistance. Among the factors produced by PLX4032-resistant melanoma cell lines, CCL2 was higher compared to the sensitive parental cell lines and increased upon drug treatment. CCL2 acted as an autocrine growth factor for melanoma cells, stimulating the proliferation and resistance to apoptosis. In patients, CCL2 is detected in melanoma cells in tumors and in plasma at levels that correlate with tumor burden and lactate dehydrogenase. Vemurafenib treatment increased the CCL2 levels in plasma, whereas the long-term clinical response was associated with low CCL2 levels. Increased CCL2 production was associated with miRNA deregulation in the resistant cells. miR-34a, miR-100 and miR-125b showed high expression in both resistant cells and in tumor biopsies that were obtained from treated patients, and they were involved in the control of cell proliferation and apoptosis. Inhibition of CCL2 and of the selected miRNAs restored both the cell apoptosis and the drug efficacy in resistant melanoma cells. Therefore, CCL2 and miRNAs are potential prognostic factors and attractive targets for counteracting treatment resistance in metastatic melanoma.