Abstract
MicroRNAs (miRNAs) are small RNAs that suppress gene expression by their interaction with 3’untranslated region of specific target mRNAs. Although the dysregulation of miRNAs has been identified in human cancer, only a few of these miRNAs have been functionally documented in breast cancer. Thus, defining the important miRNA and functional target involved in chemoresistance is an urgent need for human breast cancer treatment. In this study, we, for the first time, identified a key role of miRNA 520h (miR-520h) in drug resistance. Through protecting cells from paclitaxel-induced apoptosis, expression of miR-520h promoted the drug resistance of human breast cancer cells. Bioinformatics prediction, compensatory mutation and functional validation further confirmed the essential role of miR-520h-suppressed Death-associated protein kinase 2 (DAPK2) expression, as restoring DAPK2 abolished miR-520h-promoted drug resistance, and knockdown of DAPK2 mitigated cell death caused by the depletion of miR-520h. Furthermore, we observed that higher level of miR-520h is associated with poor prognosis and lymph node metastasis in human breast cancer patients. These results show that miR-520h is not only an independent prognostic factor, but is also a potential functional target for future applications in cancer therapeutics.
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Acknowledgements
This work was supported by the National Science Council grant from Taiwan (NSC 101-2320-B-400-016-MY3, NSC 102-2314-B-038-028-MY3, NSC 103-2314-B-038-059, NSC 101-2320-B-006-045-MY2, MOST 103-2628-B-006-003-MY3); National Health Research Institutes grant from Taiwan (CA-102-PP-41, CA-104-SP-01, CA-104-PP-12, MOHW104-TDU-B-212-124-008); Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare grant from Taiwan (103TMU-SHH-26). We thank National RNAi Core Facility (Academia Sinica, Taiwan) for providing specific shRNAs. We thank Ms Fang-Yu Tsai and Dr I-Shou Chang of Taiwan Bioinformatics Institute Core Facility for assistances on using Oncomine (National Core Facility Program for Biotechnology, NSC-100-2319-B-400-001). This research was, in part, supported by the Ministry of Education, Taiwan, R.O.C. The Aim for the Top University Project to the National Cheng Kung University (NCKU).
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Su, CM., Wang, MY., Hong, CC. et al. miR-520h is crucial for DAPK2 regulation and breast cancer progression. Oncogene 35, 1134–1142 (2016). https://doi.org/10.1038/onc.2015.168
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DOI: https://doi.org/10.1038/onc.2015.168
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