title: CCAR1 5' UTR as a natural miRancer of miR-1254 overrides tamoxifen resistance.
abstract: 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.
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Gaopeng
authors.initials: G
authors.lastname: Li
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Wenchang
authors.initials: W
authors.lastname: Qian
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Huayong
authors.initials: H
authors.lastname: Cai
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Xinbao
authors.initials: X
authors.lastname: Sun
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Pathology, Anhui Medical University, Hefei, Anhui 230027, China.
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.
authors.forename: Pengxu
authors.initials: P
authors.lastname: Qian
authors.affiliation: Department of Pathology, Anhui Medical University, Hefei, Anhui 230027, China.
authors.forename: Keshuo
authors.initials: K
authors.lastname: Ding
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Lu
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Anhui Medical University, Hefei, Anhui 230027, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Song
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Shouhong
authors.initials: S
authors.lastname: Guang
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Qingfa
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599, Singapore.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lobie
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Shan
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; C466422:AGO2 protein, human; D051017:Apoptosis Regulatory Proteins; D060565:Argonaute Proteins; C477529:CCAR1 protein, human; D018797:Cell Cycle Proteins; C558812:MIRN1254 microRNA, human; D035683:MicroRNAs; D013629:Tamoxifen