1. Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer.
- Author
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Cortez MA, Valdecanas D, Zhang X, Zhan Y, Bhardwaj V, Calin GA, Komaki R, Giri DK, Quini CC, Wolfe T, Peltier HJ, Bader AG, Heymach JV, Meyn RE, and Welsh JW
- Subjects
- Animals, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Nude, MicroRNAs genetics, Neoplasm Transplantation, Reactive Oxygen Species metabolism, Signal Transduction drug effects, Signal Transduction radiation effects, Carcinoma, Non-Small-Cell Lung therapy, Lung Neoplasms therapy, MicroRNAs metabolism, Radiation-Sensitizing Agents metabolism
- 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.
- Published
- 2014
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