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Mol Ther Nucleic Acids. 2018 Dec 7;13:556-567. doi: 10.1016/j.omtn.2018.09.025. Epub 2018 Oct 4.

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

Author information

1
Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.
2
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Ministry of Education Key Laboratory of Diagnostic Medicine, School of Laboratory Medicine, The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China; Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400046, China. Electronic address: wukecqmu@163.com.
3
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Ministry of Education Key Laboratory of Diagnostic Medicine, School of Laboratory Medicine, The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China; Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400046, China.
4
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, China Three Gorges University School of Medicine, Yichang 443002, China.
5
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Ministry of Education Key Laboratory of Diagnostic Medicine, School of Laboratory Medicine, The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China; Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400046, China; Department of Clinical Laboratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
6
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Key Laboratory of Orthopaedic Surgery of Gansu Province, First and Second Hospitals of Lanzhou University, Lanzhou 730030, China; Departments of Orthopaedic Surgery and Obstetrics and Gynecology, First and Second Hospitals of Lanzhou University, Lanzhou 730030, China.
7
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Department of Orthopaedic Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China.
8
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Department of Orthopaedic Surgery, Xiangya Second Hospital of Central South University, Changsha 410011, China.
9
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
10
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Department of Clinical Laboratory Medicine, Affiliated Hospital of Qingdao University, Qingdao 266061, China.
11
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.
12
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA; Department of Surgery, Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA.
13
Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA. Electronic address: tche@uchicago.edu.

Abstract

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 β-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.

KEYWORDS:

circular RNA; competing endogenous RNA; miRNA; miRNA decoy; miRNA inhibitor; miRNA sponge; microRNA; noncoding RNA; oncomiR

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