Volume 26, No 6, Jun 2016

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 26 Issue 6, June 2016: 655-673   |  Open Access

ORIGINAL ARTICLES

CCAR1 5′ UTR as a natural miRancer of miR-1254 overrides tamoxifen resistance

Gaopeng Li^1,*, Xiaoli Wu^1,*, Wenchang Qian^1,2, Huayong Cai¹, Xinbao Sun¹, Weijie Zhang^1,2, Sheng Tan^1,2, Zhengsheng Wu³, Pengxu Qian⁴, Keshuo Ding³, Xuefei Lu^1,2, Xiao Zhang¹, Hong Yan³, Haifeng Song⁵, Shouhong Guang^1,2, Qingfa Wu^1,2, Peter E Lobie⁶, Ge Shan^1,2 and Tao Zhu^1,2

¹The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
²Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
³Department of Pathology, Anhui Medical University, Hefei, Anhui 230027, China
⁴Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
⁵Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China
⁶Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599, Singapore Correspondence: Tao Zhu, Tel/Fax: +86 551 63601505(zhut@ustc.edu.cn)

MicroRNAs (miRNAs) typically bind to unstructured miRNA-binding sites in target RNAs, leading to a mutual repression of expression. Here, we report that miR-1254 interacts with structured elements in cell cycle and apoptosis regulator 1 (CCAR1) 5′ untranslated region (UTR) and this interaction enhances the stability of both molecules. miR-1254 can also act as a repressor when binding to unstructured sites in its targets. Interestingly, structured miR-1254-targeting sites act as both a functional RNA motif-sensing unit, and an independent RNA functional unit that enhances miR-1254 expression. Artificially designed miRNA enhancers, termed “miRancers”, can stabilize and enhance the activity of miRNAs of interest. We further demonstrate that CCAR1 5′ UTR as a natural miRancer of endogenous miR-1254 re-sensitizes tamoxifen-resistant breast cancer cells to tamoxifen. Thus, our study presents a novel model of miRNA function, wherein highly structured miRancer-like motif-containing RNA fragments or miRancer molecules specifically interact with miRNAs, leading to reciprocal stabilization.

10.1038/cr.2016.32

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