Journal
MOLECULAR THERAPY
Volume 22, Issue 8, Pages 1494-1503Publisher
CELL PRESS
DOI: 10.1038/mt.2014.79
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Funding
- Lung Cancer Research Foundation
- National Cancer Institute [K12 11111246, 9276, P01CA06294, R01s CA155196, CA160398, P50 CA070907, P30 CA016672]
- Department of Defense (BATTLE) [W81XWH-06-1-0303]
- Department of Defense (PROSPECT) [W81XWH-07-1-03060]
- Wiegand Foundation
- FAPESP [2013/20842-6]
- Cancer Prevention Research Institute of Texas (CPRIT)
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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.
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