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Blockade of miR-3614 maturation by IGF2BP3 increases TRIM25 Okadaic acid and promotes breast cancer cell proliferation
a Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, China
b Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an 710061, China
c The ART Center, Northwest women's and Children's Hospital, Xi'an, China
d The Pathology Department, Shanxi Provincial People's Hospital, Xi'an, China
Background: The cross-talk between RNA binding proteins (RBPs) and microRNAs (miRNAs) in the regulation of gene expression is a complex process. Here, we describe a new mode of regulation of TRIM25 expression medi-ated by an antagonistic interplay between IGF2BP3 and miR-3614-3p.
Methods: The expression level of TRIM25, IGF2BP3, pri-miR-3614 and miR-3614-3p in breast cancer (BC) tissues, non-tumor tissues and BC cell lines were detected by qRT-PCR, Western blot and Immunohistochemistry (IHC). Binding of miR-3614-3p and IGF2BP3 to TRIM25 RNA was verified using luciferase activation assays, RNA immu-noprecipitation (RIP) and biotin pull-down assays. In vitro and in vivo loss- and gain-of-function studies were performed to reveal the effects and related mechanism of IGF2BP3-miR-3614-3p-TRIM25 axis in in breast cancer cells proliferation.
Findings: We found that an intragenic miRNA-3614-3p inhibits the expression of its host gene TRIM25 by binding to its 3′- untranslated region (UTR). Interestingly, IGF2BP3 can competitively occupy this binding site and inhibit miRNA-3614 maturation, thereby protecting TRIM25 mRNA from miR-3614-mediated degradation. The overex-pression of miR-3614-3p dramatically inhibited breast cancer cell growth through the downregulation of TRIM25. Furthermore, the silencing of IGF2BP3 reduced TRIM25 expression, suppressed cell proliferation, and ex-hibited a synergistic effect with miR-3614-3p overexpression.
Interpretation: Collectively, these results demonstrate that control of TRIM25 RNA by an interplay between IGF2BP3 and miR-3614-3p represents a mechanism for breast cancer cell proliferation.
Fund: The scientific research and sharing platform construction project of Shaanxi Province, Opening Project of Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, China Postdoctoral Science Foundation and The National Natural Science Foundation of China.
© 2018 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Post-transcriptional gene regulation (PTGR) involves complex processes that modulate the transcription, transport, maturation, trans-lation, and stability of coding and non-coding RNAs [1,2]. Post-transcriptional modifications can have profound effects on gene
Corresponding authors at: Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, China.
Correspondence to: Y. Chen, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an 710061, China. E-mail addresses: [email protected] (Y. Chen), [email protected] (A. Li),
[email protected] (C. Huang).
1 These two authors contributed equally to this work.
expression; RNA-binding proteins (RBPs) and microRNAs (miRNAs) are potent post-transcriptional regulators of gene expression. Most commonly, they converge at the 3′-UTRs of mRNAs and affect the stabil-ity and translation of the transcripts [3,4].