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Hsa_Circ_0053943 Drives Uveal Melanoma Progression via Regulating N6-Methyladenosine Modification of EGFR with IGF2BP3
52 Pages Posted: 6 Jun 2022
More...Abstract
Background: Increasing studies characterized the critical role of circular RNAs (circRNAs) as regulatory factors in the progression of multiple cancers. Nevertheless, the biological functions of circRNAs and their underlying molecular mechanisms in uveal melanoma (UM) progression remain enigmatic.
Methods: A novel circRNA, circ_0053943, was selected from re-mining UM microarray and quantitative RT-PCR. Functional assays were performed to investigate the roles of circ_0053943 in UM progression both in vitro and in vivo. To further explore the molecular mechanisms of circ_0053943 in UM, we implemented the fluorescence in situ hybridization, RNA pulldown assay, RNA binding protein immunoprecipitation assay, RNA sequencing, co-immunoprecipitation, and dual-luciferase reporter assays.
Findings: Circ_0053943 was upregulated in UM and prompted the proliferation and metastatic ability of UM cells in vitro and in vivo. Mechanistically, circ_0053943 could bind to the KH1 and KH2 domains of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), enhancing the function of IGF2BP3 by facilitating the stabilization of target mRNA. RNA sequencing assay identified epidermal growth factor receptor (EGFR) as a target gene of circ_0053943 and IGF2BP3 at the transcriptional level. Rescue assays revealed that circ_0053943 exerts its biologic function by stabilizing EGFR mRNA and regulating downstream the MAPK/ERK signaling pathway.
Interpretation: Circ_0053943 may promote UM progression by stabilizing EGFR mRNA and activating the MAPK/ERK signaling pathway through forming a circ_0053943/IGF2BP3/EGFR RNA-protein ternary complex, which in turn provide a potential biomarker and therapeutic target for UM.
Funding: This work is supported by the National Natural Science Foundation of China (Grant No.82171838), Provincial Science and Technology Department Social Development Plan (Grant No. BE2020722).
Declaration of Interest: The authors declare that they have no competing interests.
Ethical Approval: All experimental protocols were approved by the Ethics Committee of Nanjing Medical University and performed in accordance with the relevant guidelines and regulations. Written informed consents were obtained from all patients. All animal experiments were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (No. IACUC-2108017).
Keywords: uveal melanoma, hsa_circ_0053943, IGF2BP3, EGFR, MAPK/ERK signaling pathway
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