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Abstract
Radioresistance hampers success in the treatment of patients with advanced colorectal cancer (CRC). Improving our understanding of the underlying mechanisms of radioresistance could increase patients’ response to irradiation (IR). MicroRNAs are a class of small RNAs involved in tumor therapy response to radiation. Here we found that miR-214 was markedly decreased in CRC cell lines and blood of CRC patients after IR exposure. Meanwhile, autophagy was enhanced in irradiated CRC cells. Mechanically, ATG12 was predicted and identified as a direct target of miR-214 by dual luciferase assay, qPCR, and Western blot. In vitro and in vivo experiments showed that miR-214 promoted radiosensitivity by inhibiting IR-induced autophagy. Restoration of ATG12 attenuated miR-214-mediated inhibition of cell growth and survival in response to IR. Importantly, miR-214 was highly expressed in radiosensitive CRC specimens and negatively correlated with plasma level of CEA. Moreover, ATG12 and LC3 expressions were increased in radioresistant CRC specimens. Our study elucidates that miR-214 promotes radiosensitivity by inhibition of ATG12-mediated autophagy in CRC. Importantly, miR-214 is a determinant of CRC irradiation response and may serve as a potential therapeutic target in CRC treatment.
Highlights
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide[1]
Results miR-214 is downregulated in response to IR To identify miRNAs that regulate the IR response in CRC, a miRNA screen was performed in CRC cells treated with IR in our previous study[12]
From the list of differentially expressed miRNAs, we focused on miR-214 because it was decreased most significantly in irradiated CRC cells (Fig. 1a), and its role in IR response of CRC is unclear
Summary
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide[1]. Surgical resection remains the only curative treatment that is available for CRC. 20 to 40% of CRC patients harbor a locally advanced, unresectable, nonmetastatic disease termed “locally advanced CRC” at the time of diagnosis. Due to the inherent ability of CRC to become chemotherapy and radiation resistant, the combined-modality therapy has failed to universally improve patients’ prognosis. Because radioresistance contributes significantly to challenges in the treatment of CRC, understanding the potential molecular mechanism underlying radiosensitivity or radioresistance may improve therapeutic outcomes
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