Purpose The oncogenic miR-155 is upregulated in many human cancers and its expression is increased in more aggressive and therapy resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia and acute lymphoblastic leukemia. Results We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism, and demonstrate that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions Our findings support the existence of a miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death.
Combining anti-miR-155 with chemotherapy for the treatment of lung cancers / K. Van Roosbroeck, F. Fanini, T. Setoyama, C. Ivan, C. Rodriguez Aguayo, E. Fuentes Mattei, L. Xiao, I. Vannini, R. Redis, L. D'Abundo, X. Zhang, M.S. Nicoloso, S. Rossi, V. Gonzalez Villasana, R. Rupaimoole, M. Ferracin, F. Morabito, A. Neri, P. Ruvolo, V.R. Ruvolo, C.V. Pecot, D. Amadori, L. Aruzzo, S. Calin, X. Wang, M.J. You, A. Ferrajoli, R.Z. Orlowski, W. Plunkett, T. Lichtenberg, R.V. Davuluri, I. Berindan Neagoe, M. Negrini, I.I. Wistuba, K. Hagop, A.K. Sood, G. Lopez Berestein, M.J. Keating, M. Fabbri, G.A. Calin. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - (2016). [Epub ahead of print] [10.1158/1078-0432.CCR-16-1025]
Combining anti-miR-155 with chemotherapy for the treatment of lung cancers
A. Neri;
2016
Abstract
Purpose The oncogenic miR-155 is upregulated in many human cancers and its expression is increased in more aggressive and therapy resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia and acute lymphoblastic leukemia. Results We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism, and demonstrate that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions Our findings support the existence of a miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death.File | Dimensione | Formato | |
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