Artigo
Therapeutic Delivery of miR-200c Enhances Radiosensitivity in Lung Cancer
Registro en:
Molecular Therapy. New York: Nature Publishing Group, v. 22, n. 8, p. 1494-1503, 2014.
1525-0016
10.1038/mt.2014.79
WOS:000339780000014
Autor
Cortez, Maria Angelica
Valdecanas, David
Zhang, Xiaochun
Zhan, Yanai
Bhardwaj, Vikas
Calin, George A.
Komaki, Ritsuko
Giri, Dipak K.
Quini, Caio C. [UNESP]
Wolfe, Tatiana
Peltier, Heidi J.
Bader, Andreas G.
Heymach, John V.
Meyn, Raymond E.
Welsh, James W.
Resumen
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. Lung Cancer Research Foundation National Cancer Institute Department of Defense (BATTLE) Department of Defense (PROSPECT) Wiegand Foundation Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Cancer Prevention Research Institute of Texas (CPRIT) Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA Sipaumdi Pathol Consultancy, Pearland, TX USA Sao Paulo State Univ UNESP, Dept Phys & Biophys, Botucatu, SP, Brazil Mirna Therapeut Inc, Austin, TX USA Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA Sao Paulo State Univ UNESP, Dept Phys & Biophys, Botucatu, SP, Brazil National Cancer InstituteK12 11111246 National Cancer Institute9276 National Cancer InstituteP01CA06294 National Cancer InstituteR01s CA155196 National Cancer InstituteCA160398 National Cancer InstituteP50 CA070907 National Cancer InstituteP30 CA016672 Department of Defense (BATTLE)W81XWH-06-1-0303 Department of Defense (PROSPECT)W81XWH-07-1-03060 FAPESP: 13/20842-6