Therapeutic Delivery of miR-200c Enhances Radiosensitivity in Lung Cancer

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Cortez, Maria Angelica ^[1] ; Valdecanas, David ^[1] ; Zhang, Xiaochun ^[1] ; Zhan, Yanai ^[2] ; Bhardwaj, Vikas ^[1] ; Calin, George A. ^[3] ; Komaki, Ritsuko ^[4] ; Giri, Dipak K. ^[5] ; Quini, Caio C. ^[6] ; Wolfe, Tatiana ^[1] ; Peltier, Heidi J. ^[7] ; Bader, Andreas G. ^[7] ; Heymach, John V. ^[8] ; Meyn, Raymond E. ^[1] ; Welsh, James W. ^[4]

Afiliação do(s) autor(es)

^[1] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 - USA

^[2] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 - USA

^[3] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 - USA

^[4] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 - USA

^[5] Sipaumdi Pathol Consultancy, Pearland, TX - USA

^[6] Sao Paulo State Univ UNESP, Dept Phys & Biophys, Botucatu, SP - Brazil

^[7] Mirna Therapeut Inc, Austin, TX - USA

^[8] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 - USA

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR THERAPY; v. 22, n. 8, p. 1494-1503, AUG 2014.
• Citações Web of Science: 80

Resumo

The microRNA (miR)-200s and their negative regulator ZEB1 have been extensively studied in the context of the epithelial mesenchymal transition. Loss of miR-200s has been shown to enhance cancer aggressiveness and metastasis, whereas replacement of miR-200 miRNAs has been shown to inhibit cell growth in several types of tumors, including lung cancer. Here, we reveal a novel function of miR-200c, a member of the miR-200 family, in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative, stress such as radiation. We found that miR-200c overexpression increased cellular radiosensitivity by direct regulation of the oxidative stress response genes PRDX2, GAPB/Nrf2, and SESN1 in ways that inhibits DNA double-strand breaks repair, increase levels of reactive oxygen species, and upregulate p21. We used a lung cancer xenograft model to further demonstrate the therapeutic potential of systemic delivery of miR-200c to enhance radiosensitivity in lung cancer. Our findings suggest that the antitumor effects of miR-200c result partially from its regulation of the oxidative stress response; they further suggest that miR-200c, in combination with radiation, could represent a therapeutic strategy in the future. (AU)

• Processo FAPESP: 13/20842-6 - Avaliação da influência do câncer de pâncreas nas funções metabólicas hepática e renal
• Beneficiário: Caio César Quini
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado