A Simplified System to Express Circularized Inhibitors of miRNA for Stable and Potent Suppression of miRNA Functions

作     者：Shu, Yi Wu, Ke Zeng, Zongyue Huang, Shifeng Ji, Xiaojuan Yuan, Chengfu Zhang, Linghuan Liu, Wei Huang, Bo Feng, Yixiao Zhang, Bo Dai, Zhengyu Shen, Yi Luo, Wenping Wang, Xi Liu, Bo Lei, Yan Ye, Zhenyu Zhao, Ling Cao, Daigui Yang, Lijuan Chen, Xian Luu, Hue H. Reid, Russell R. Wolf, Jennifer Moriatis Lee, Michael J. He, Tong-Chuan 

作者机构：Chongqing Med Univ Stem Cell Biol & Therapy Lab Minist Educ Key Lab Child Dev & DisordersChildrens Hosp Chongqing 400014 Peoples R China Univ Chicago Med Ctr Mol Oncol Lab Dept Orthopaed Surg & Rehabil Med 5841 South Maryland AveMC 3079 Chicago IL 60637 USA Chongqing Med Univ Minist Educ Key Lab Diagnost Med Sch Lab MedAffiliated Hosp Chongqing 400016 Peoples R China Chongqing Med Univ Sch Pharm Dept Pharmacol Chongqing 400046 Peoples R China China Three Gorges Univ Dept Biochem & Mol Biol Sch Med Yichang 443002 Peoples R China Nanchang Univ Dept Clin Lab Med Affiliated Hosp 2 Nanchang 330006 Jiangxi Peoples R China Lanzhou Univ Key Lab Orthopaed Surg Gansu Prov Hosp 1 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Key Lab Orthopaed Surg Gansu Prov Hosp 2 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Dept Orthopaed Surg Hosp 1 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Dept Obstet & Gynecol Hosp 1 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Dept Orthopaed Surg Hosp 2 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Dept Obstet & Gynecol Hosp 2 Lanzhou 730030 Gansu Peoples R China Chongqing Hosp Tradit Chinese Med Dept Orthopaed Surg Chongqing 400021 Peoples R China Cent S Univ Dept Orthopaed Surg Xiangya Hosp 2 Changsha 410011 Hunan Peoples R China Soochow Univ Dept Gen Surg Affiliated Hosp 2 Suzhou 215004 Peoples R China Qingdao Univ Dept Clin Lab Med Affiliated Hosp Qingdao 266061 Peoples R China Univ Chicago Med Ctr Dept Surg Sect Plast Surg Chicago IL 60637 USA 

出 版 物：《MOLECULAR THERAPY-NUCLEIC ACIDS》 (Mol. Ther. Nucl. Acids)

年 卷 期：2018年第13卷

页      面：556-567页

核心收录：

基　　金：NIH [CA226303, DE020140] U.S. Department of Defense [OR130096] Chicago Biomedical Consortium Searle Funds at The Chicago Community Trust Scoliosis Research Society National Key Research and Development Program of China [2016YFC1000803, 2011CB707906] China Scholarship Council University of Chicago Cancer Center Support Grant [P30CA014599] National Center for Advancing Translational Sciences of the NIH [UL1 TR000430] Mabel Green Myers Research Endowment Fund The University of Chicago Orthopaedic Surgery Alumni Fund 

主　　题：microRNA miRNA miRNA sponge circular RNA miRNA inhibitor competing endogenous RNA miRNA decoy noncoding RNA oncomiR 

摘      要：MicroRNAs (miRNAs) are an evolutionarily conserved class of small regulatory noncoding RNAs, binding to complementary target mRNAs and resulting in mRNA translational inhibition or degradation, and they play an important role in regulating many aspects of physiologic and pathologic processes in mammalian cells. Thus, efficient manipulations of miRNA functions may be exploited as promising therapeutics for human diseases. Two commonly used strategies to inhibit miRNA functions include direct transfection of chemically synthesized miRNA inhibitors and delivery of a gene vector that instructs intracellular transcription of miRNA inhibitors. While most miRNA inhibitors are based on antisense molecules to bind and sequester miRNAs from their natural targets, it is challenging to achieve effective and stable miRNA inhibition. Here we develop a user-friendly system to express circular inhibitors of miRNA (CimiRs) by exploiting the noncanonical head-to-tail backsplicing mechanism for generating endogenous circular RNA sponges. In our proof-of-principle experiments, we demonstrate that the circular forms of the hsa-miR223-binding site of human beta-arrestin1 (ARRB1) 3 UTR sponge RNA (BUTR), the bulged anti-miR223 (cirBulg223) and bulged anti-miR21 (cirBulg21), exhibit more potent suppression of miRNA functions than their linear counterparts. Therefore, the engineered CimiR expression system should be a valuable tool to target miRNAs for basic and translational research.