title: Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer.
abstract: 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.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Maria Angelica
authors.initials: MA
authors.lastname: Cortez
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: David
authors.initials: D
authors.lastname: Valdecanas
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yanai
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhardwaj
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komaki
authors.affiliation: Sipaumdi Pathology Consultancy, Pearland, Texas, USA.
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Giri
authors.affiliation: Department of Physics and Biophysics, Sao Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil.
authors.forename: Caio C
authors.initials: CC
authors.lastname: Quini
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Wolfe
authors.affiliation: Mirna Therapeutics, Inc., Austin, Texas, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Peltier
authors.affiliation: Mirna Therapeutics, Inc., Austin, Texas, USA.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Bader
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Meyn
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address: jwelsh@mdanderson.org.
authors.forename: James W
authors.initials: JW
authors.lastname: Welsh
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species