circRARS synergises with IGF2BP3 to regulate RNA methylation recognition to promote tumour progression in renal cell carcinoma.

Publisher: Wiley Country of Publication: United States NLM ID: 101597971 Publication Model: Print Cited Medium: Internet ISSN: 2001-1326 (Electronic) Linking ISSN: 20011326 NLM ISO Abbreviation: Clin Transl Med Subsets: MEDLINE

Publication: 2020- : [Hoboken, NJ] : Wiley
Original Publication: Heidelberg : Springer-Verlag

Carcinoma, Renal Cell*/genetics ; Kidney Neoplasms*/genetics; Humans ; Calpain ; Cell Transformation, Neoplastic ; Protein Inhibitors of Activated STAT ; RNA Methylation ; RNA, Circular/genetics

As the most prominent RNA modification, N6-methyladenosine (m ⁶ A) participates in the regulation of tumour initiation and progression. Circular RNAs (circRNAs) also play crucial roles in ubiquitous life processes. Whether circRNAs are required for m ⁶ A regulation in renal cell carcinoma (RCC) remains unclear. Meta-analysis and bioinformatics identified that IGF2BP3 was upregulated in RCC and indicated a worse prognosis. IGF2BP3 significantly promoted RCC progression in vitro and in vivo. Mechanistically, circRARS bound to KH1-KH2 domains of IGF2BP3 to enhance m ⁶ A modification recognition. A 12-nt sequence (GUCUUCCAGCAA) was proven to be the IGF2BP3-binding site of circRARS. Additionally, CAPN15, CD44, HMGA2, TNRC6A and ZMIZ2 were screened to be the target genes regulated by the IGF2BP3/circRARS complex in an m ⁶ A-dependent manner. Stabiliser proteins, including HuR, Matrin3 and pAbPC1, were recruited by circRARS, thereby increasing the mRNA stability of the forementioned five target genes. Consequently, the IGF2BP3/circRARS complex facilitated the lipid accumulation of RCC cells and promoted sunitinib resistance via target genes. circRARS synergised with IGF2BP3 to facilitate m ⁶ A recognition, thereby promoting RCC progression. Thus, IGF2BP3 could be a potential biomarker for RCC diagnosis and prognosis and a therapeutic target.
(© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

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82103000 National Natural Science Foundation of China; 81672528 National Natural Science Foundation of China; 81874090 National Natural Science Foundation of China; 81972630 National Natural Science Foundation of China; 81927807 National Key Scientific Instrument Development Project; 2021M691154 China Postdoctoral Science Foundation; 2022M711261 China Postdoctoral Science Foundation; JCYJ20190809102415054 Science, Technology and Innovation Commission of Shenzhen Municipality

Keywords: IGF2BP3; circRARS; m6A methylation; renal cell carcinoma; tumour progression

EC 3.4.22.- (Calpain)
EC 3.4.22.- (CAPN15 protein, human)
0 (Protein Inhibitors of Activated STAT)
0 (RNA, Circular)
0 (ZMIZ2 protein, human)
0 (IGF2BP3 protein, human)

Date Created: 20231211 Date Completed: 20231220 Latest Revision: 20240417

20250114

PMC10711645

10.1002/ctm2.1512

38073586