Blockade of miR-3614 maturation by IGF2BP3 increases TRIM25 expression and promotes breast cancer cell proliferation

Abstract

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 mediated 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 immunoprecipitation (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 overexpression 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 exhibited 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.

IGF2BP3 May Contributes to Lung Tumorigenesis by Regulating the Alternative Splicing of PKM

“…Moreover, multiple evidences proved that IGF2BP3 is relate to the processes of cancer development and prognosis ( Lochhead et al, 2012 ; Cao et al, 2018 ). Given these foundations, some researches have been performed to comprehensively understand the functions of IGF2BP3 ( Cao et al, 2018 ; Mancarella et al, 2018 ; Wang et al, 2019 ).…”

“…In addition it’s the key role in fetal and adult hemoglobin expression ( Tangprasittipap et al, 2018 ). It has been identified that IGF2BP3 can inhibit miRNA-3614 maturation thereby increased TRIM25 expression and promotes the cell proliferation of breast cancer ( Wang et al, 2019 ). Studies showed that IGF2BP3 can induce cell proliferation and invasion through post-transcriptional regulation of IGF2 and promotes lung tumorigenesis via attenuating P53 stability which give us a hint to do more research on it ( Taniuchi et al, 2014 ; Zhao et al, 2017 ).…”

IGF2BP3 From Physiology to Cancer: Novel Discoveries, Unsolved Issues, and Future Perspectives

“…Both RBPs and miRNAs converge on the 3 -UTR of mRNAs, and the juxtaposition of their binding contributes to the combinatorial mechanisms of posttranscriptional gene regulation with a relevant impact on cellular fate and behavior. IGF2BP3 promotes mRNA stability/degradation by interacting with miRNAs through different processes as follows: (1) IGF2BP3 may protect target mRNAs from miRNA-dependent degradation by segregating transcripts into cytoplasmic RNP granules that do not contain RISC (Jonson et al, 2014); (2) IGF2BP3 may modulate the association between target transcripts and RISC (Ennajdaoui et al, 2016); (3) IGF2BP3 may compete with miRNAs for common binding sites on the 3 -UTRs of target transcripts (Ennajdaoui et al, 2016); and (4) IGF2BP3 may affect miRNA biogenesis, thus indirectly affecting the fate of miRNA targets (Wang et al, 2019).…”

“…Overall, IGF2BP3 influences the expression of malignancyassociated RNAs by modulating their interactions with miRNAs through multiple and complex mechanisms, including the recently identified effect on miRNA maturation (Wang et al, 2019). During this process, IGF2BP3 competes with the ribonuclease Drosha to bind to pri-miRNAs in the nucleus, thus avoiding miRNA maturation and indirectly favoring the stability of miRNA transcript targets.…”

Small Nucleolar RNA and Small Nucleolar RNA Host Gene Signatures as Biomarkers for Pancreatic Cancer

“…A recent report showed that SNORD17 was functionally related to a speci c active gene TRIM25 [27]. Wang et al [28] demonstrated that the control of TRIM25 RNA by an interplay between IGF2BP3 and miR-3614-3p represents a mechanism for breast cancer cell proliferation. More notably, Li et al [29] reported that suppression of TRIM25 expression using high levels of miR-873 dictates MTA1 protein upregulation in hepatocellular carcinoma.…”