IGF2BP3 Regulates the Expression of RRM2 and Promotes the Progression of Rheumatoid Arthritis Via RRM2/Akt/MMP-9 Pathway

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2024 May 31

PMID 38820515

Authors

Zhaonan Ban

Zhengjiang Li

Shuxing Xing

Yongjie Ye

Affiliations

Soon will be listed here.

Abstract

Background: Rheumatoid arthritis (RA) is a common inflammatory and autoimmune disease. Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) is a crucial and a rate-limiting enzyme responsible for deoxynucleotide triphosphate(dNTP) production. We have found a high expression level of RRM2 in patients with RA, but the molecular mechanism of its action remains unclear.

Methods: We analyzed the expression of hub genes in RA using GSE77298 datasets downloaded from Gene Expression Omnibus database. RRM2 and insulin-like growth factor-2 messenger ribonucleic acid (mRNA)-binding protein 3 (IGF2BP3) gene knockdown was achieved by infection with lentiviruses. The expression of RRM2, IGF2BP3, matrix metalloproteinase (MMP)-1, and MMP-9 were detected via western blotting assay. Cell viability was detected via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. MeRIP-qRT-PCR was performed to test the interaction of IGF2BP3 and RRM2 mRNA via m6A modification. Cell proliferation was determined by clone formation assay. Migration and invasion assays were performed using transwell Boyden chamber.

Results: RRM2 and IGF2BP3 were highly expressed in clinical specimens and tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β-stimulated synovial cells. RRM2 and IGF2BP3 knockdown inhibited the proliferation, migration, and invasion of MH7A cells. The inhibitory effects of IGF2BP3 knockdown were effectively reversed by simultaneously overexpressing RRM2 in MH7A cells. By analyzing N6-methyladenosine (m6A)2Target database, five m6A regulatory target binding sites for IGF2BP3 were identified in RRM2 mRNA, suggesting a direct relationship between IGF2BP3 and RRM2 mRNA. Additionally, in RRM2 small hairpin (sh)RNA lentivirus-infected cells, the levels of phosphorylated Akt and MMP-9 were significantly decreased compared with control shRNA lentivirus-infected cells.

Conclusion: The present study demonstrated that RRM2 promoted the Akt phosphorylation leading to high expression of MMP-9 to promote the migration and invasive capacities of MH7A cells. Overall, IGF2BP promotes the expression of RRM2, and regulates the migration and invasion of MH7A cells via Akt/MMP-9 pathway to promote RA progression.

Citing Articles

Deciphering hub genes and immune landscapes related to neutrophil extracellular traps in rheumatoid arthritis: insights from integrated bioinformatics analyses and experiments.

Li Y, Liu J, Sun Y, Hu Y, Zhou Q, Cong C Front Immunol. 2025; 15:1521634.

PMID: 39845946 PMC: 11750673. DOI: 10.3389/fimmu.2024.1521634.

Citrullinated IGF2BP1 promotes rheumatoid synovial aggression via increasing the mRNA stability of SEMA3D.

Qin Y, Liu L, Zhang Y, Chen X, Zhang J, Ling S Commun Biol. 2025; 8(1):50.

PMID: 39809921 PMC: 11732996. DOI: 10.1038/s42003-025-07492-3.

References

Cao X, Xue F, Chen H, Shen L, Yuan X, Yu Y . MiR-202-3p inhibits the proliferation and metastasis of lung adenocarcinoma cells by targeting RRM2. Ann Transl Med. 2023; 10(24):1374. PMC: 9843311. DOI: 10.21037/atm-22-6089. View

Wang X, Wang X, Sun J, Fu S . An enhanced RRM2 siRNA delivery to rheumatoid arthritis fibroblast-like synoviocytes through a liposome‑protamine-DNA-siRNA complex with cell permeable peptides. Int J Mol Med. 2018; 42(5):2393-2402. PMC: 6192755. DOI: 10.3892/ijmm.2018.3815. View

Cai H, Guo H, Deng Y, Jiang J, Liu S, He W . RRM2 regulates osteogenesis of mouse embryo fibroblasts via the Wnt/β‑catenin signaling pathway. Exp Ther Med. 2022; 24(4):605. PMC: 9468855. DOI: 10.3892/etm.2022.11542. View

Hu Y, Zhao X . Role of m6A in osteoporosis, arthritis and osteosarcoma (Review). Exp Ther Med. 2021; 22(3):926. PMC: 8281110. DOI: 10.3892/etm.2021.10358. View

Mo X, Zhang Y, Lei S . Genome-Wide Identification of N-Methyladenosine (mA) SNPs Associated With Rheumatoid Arthritis. Front Genet. 2018; 9:299. PMC: 6085591. DOI: 10.3389/fgene.2018.00299. View

Meznerics F, Kemeny L, Gunther E, Bako E, Dembrovszky F, Szabo B . Multibiomarker disease activity score: an objective tool for monitoring rheumatoid arthritis? A systematic review and meta-analysis. Rheumatology (Oxford). 2022; 62(6):2048-2059. PMC: 10234206. DOI: 10.1093/rheumatology/keac715. View

Zhang X, Li X, Jia H, An G, Ni J . The mA methyltransferase METTL3 modifies PGC-1α mRNA promoting mitochondrial dysfunction and oxLDL-induced inflammation in monocytes. J Biol Chem. 2021; 297(3):101058. PMC: 8406003. DOI: 10.1016/j.jbc.2021.101058. View

Tesolin P, Bertinetto F, Sonaglia A, Cappellani S, Concas M, Morgan A . High Throughput Genetic Characterisation of Caucasian Patients Affected by Multi-Drug Resistant Rheumatoid or Psoriatic Arthritis. J Pers Med. 2022; 12(10). PMC: 9605087. DOI: 10.3390/jpm12101618. View

Thakur S, Riyaz B, Patil A, Kaur A, Kapoor B, Mishra V . Novel drug delivery systems for NSAIDs in management of rheumatoid arthritis: An overview. Biomed Pharmacother. 2018; 106:1011-1023. DOI: 10.1016/j.biopha.2018.07.027. View

10.

Yao F, Xu C, Gao Y, Fu B, Zhang L, Guo Y . Expression and clinical significance of the m6A reader in peripheral blood mononuclear cells from rheumatoid arthritis patients. J Immunotoxicol. 2022; 19(1):53-60. DOI: 10.1080/1547691X.2022.2067916. View

11.

Han J, Hu J, Sun F, Bian H, Tang B, Fang X . MicroRNA-20a-5p suppresses tumor angiogenesis of non-small cell lung cancer through RRM2-mediated PI3K/Akt signaling pathway. Mol Cell Biochem. 2020; 476(2):689-698. DOI: 10.1007/s11010-020-03936-y. View

12.

Qin Y, Li L, Luo E, Hou J, Yan G, Wang D . Role of m6A RNA methylation in cardiovascular disease (Review). Int J Mol Med. 2020; 46(6):1958-1972. PMC: 7595665. DOI: 10.3892/ijmm.2020.4746. View

13.

Tsuchiya H, Fujio K . Title Current Status of the Search for Biomarkers for Optimal Therapeutic Drug Selection for Patients with Rheumatoid Arthritis. Int J Mol Sci. 2021; 22(17). PMC: 8431405. DOI: 10.3390/ijms22179534. View

14.

Xia J, Zhang L, Gu T, Liu Q, Wang Q . Identification of ferroptosis related markers by integrated bioinformatics analysis and In vitro model experiments in rheumatoid arthritis. BMC Med Genomics. 2023; 16(1):18. PMC: 9887825. DOI: 10.1186/s12920-023-01445-7. View

15.

Boyadzhieva V, Tachkov K, Stoilov N, Mitov K, Stoilov R, Petrova G . Quality of life and disease activity of patients with rheumatoid arthritis on tofacitinib and biologic disease-modifying antirheumatic drug therapies. Rheumatol Int. 2022; 42(10):1775-1783. DOI: 10.1007/s00296-022-05163-8. View

16.

Jin C, Du L, Nuerlan A, Wang X, Yang Y, Guo R . High expression of RRM2 as an independent predictive factor of poor prognosis in patients with lung adenocarcinoma. Aging (Albany NY). 2021; 13(3):3518-3535. PMC: 7906179. DOI: 10.18632/aging.202292. View

17.

Jiao Y, Li Y, Zhang J, Zhang S, Zha Y, Wang J . RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway. Biomolecules. 2022; 12(2). PMC: 8869767. DOI: 10.3390/biom12020299. View

18.

Zhou Z, Song Q, Yang Y, Wang L, Wu Z . Comprehensive Landscape of RRM2 with Immune Infiltration in Pan-Cancer. Cancers (Basel). 2022; 14(12). PMC: 9221307. DOI: 10.3390/cancers14122938. View

19.

Shen Q, Du Y . A comprehensive review of advanced drug delivery systems for the treatment of rheumatoid arthritis. Int J Pharm. 2023; 635:122698. DOI: 10.1016/j.ijpharm.2023.122698. View

20.

Wu B, Peng R, Chen Y, Zhong J, Zhong S, Wang B . Identification of RRM2 in peripheral blood mononuclear cells as a novel biomarker for the diagnosis of rheumatoid arthritis. Clin Exp Rheumatol. 2022; 40(11):2109-2118. DOI: 10.55563/clinexprheumatol/ixdaek. View