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Mol Ther. 2014 Aug;22(8):1494-503. doi: 10.1038/mt.2014.79. Epub 2014 May 5.

Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer.

Author information

1
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
2
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
3
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
5
Sipaumdi Pathology Consultancy, Pearland, Texas, USA.
6
Department of Physics and Biophysics, Sao Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil.
7
Mirna Therapeutics, Inc., Austin, Texas, USA.
8
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

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.

PMID:
24791940
PMCID:
PMC4435581
DOI:
10.1038/mt.2014.79
[Indexed for MEDLINE]
Free PMC Article
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