IDH1 Mutation Produces R-2-hydroxyglutarate (R-2HG) and Induces Mir-182-5p Expression to Regulate Cell Cycle and Tumor Formation in Glioma

Overview

Journal Biol Res

Specialty Biology

Date 2024 May 17

PMID 38760850

Authors

Haiting Zhao

Li Meng

Peng Du

Xinbin Liao

Xin Mo

Mengqi Gong

Jiaxin Chen

Yiwei Liao

Affiliations

Soon will be listed here.

Abstract

Background: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its regulatory mechanism in glioma remains incompletely understood.

Results: miR-182-5p expression was increased within IDH1-mutant glioma specimens according to TCGA, CGGA, and online dataset GSE119740, as well as collected clinical samples. (R)-2-hydroxyglutarate ((R)-2HG) treatment up-regulated the expression of miR-182-5p, enhanced glioma cell proliferation, and suppressed apoptosis; miR-182-5p inhibition partially eliminated the oncogenic effects of R-2HG upon glioma cells. By direct binding to Cyclin Dependent Kinase Inhibitor 2 C (CDKN2C) 3'UTR, miR-182-5p inhibited CDKN2C expression. Regarding cellular functions, CDKN2C knockdown promoted R-2HG-treated glioma cell viability, suppressed apoptosis, and relieved cell cycle arrest. Furthermore, CDKN2C knockdown partially attenuated the effects of miR-182-5p inhibition on cell phenotypes. Moreover, CDKN2C knockdown exerted opposite effects on cell cycle check point and apoptosis markers to those of miR-182-5p inhibition; also, CDKN2C knockdown partially attenuated the functions of miR-182-5p inhibition in cell cycle check point and apoptosis markers. The engineered CS-NPs (antagomir-182-5p) effectively encapsulated and delivered antagomir-182-5p, enhancing anti-tumor efficacy in vivo, indicating the therapeutic potential of CS-NPs(antagomir-182-5p) in targeting the miR-182-5p/CDKN2C axis against R-2HG-driven oncogenesis in mice models.

Conclusions: These insights highlight the potential of CS-NPs(antagomir-182-5p) to target the miR-182-5p/CDKN2C axis, offering a promising therapeutic avenue against R-2HG's oncogenic influence to glioma.

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References

Liu Y, Lu Y, Celiku O, Li A, Wu Q, Zhou Y . Targeting IDH1-Mutated Malignancies with NRF2 Blockade. J Natl Cancer Inst. 2019; 111(10):1033-1041. PMC: 6792082. DOI: 10.1093/jnci/djy230. View

Lai W, Lin M . Nucleic acid delivery with chitosan and its derivatives. J Control Release. 2008; 134(3):158-68. DOI: 10.1016/j.jconrel.2008.11.021. View

Zhang H, Pan X, Wu Q, Guo J, Wang C, Liu H . Manganese carbonate nanoparticles-mediated mitochondrial dysfunction for enhanced sonodynamic therapy. Exploration (Beijing). 2023; 1(2):20210010. PMC: 10190974. DOI: 10.1002/EXP.20210010. View

Zhou Q, Liu J, Quan J, Liu W, Tan H, Li W . MicroRNAs as potential biomarkers for the diagnosis of glioma: A systematic review and meta-analysis. Cancer Sci. 2018; 109(9):2651-2659. PMC: 6125451. DOI: 10.1111/cas.13714. View

Figueroa M, Abdel-Wahab O, Lu C, Ward P, Patel J, Shih A . Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010; 18(6):553-67. PMC: 4105845. DOI: 10.1016/j.ccr.2010.11.015. View

Li J, Yuan H, Xu H, Zhao H, Xiong N . Hypoxic Cancer-Secreted Exosomal miR-182-5p Promotes Glioblastoma Angiogenesis by Targeting Kruppel-like Factor 2 and 4. Mol Cancer Res. 2020; 18(8):1218-1231. DOI: 10.1158/1541-7786.MCR-19-0725. View

Singh S, Narang A, Mahato R . Subcellular fate and off-target effects of siRNA, shRNA, and miRNA. Pharm Res. 2011; 28(12):2996-3015. DOI: 10.1007/s11095-011-0608-1. View

Grubbs E, Williams M, Scheet P, Vattathil S, Perrier N, Lee J . Role of CDKN2C Copy Number in Sporadic Medullary Thyroid Carcinoma. Thyroid. 2016; 26(11):1553-1562. PMC: 6453497. DOI: 10.1089/thy.2016.0224. View

Zhu L, Lu Z, Zhao H . Antitumor mechanisms when pRb and p53 are genetically inactivated. Oncogene. 2014; 34(35):4547-57. PMC: 4459916. DOI: 10.1038/onc.2014.399. View

10.

Kara G, Calin G, Ozpolat B . RNAi-based therapeutics and tumor targeted delivery in cancer. Adv Drug Deliv Rev. 2022; 182:114113. DOI: 10.1016/j.addr.2022.114113. View

11.

Di Fiore R, DAnneo A, Tesoriere G, Vento R . RB1 in cancer: different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis. J Cell Physiol. 2013; 228(8):1676-87. DOI: 10.1002/jcp.24329. View

12.

Zhao M, Li A, Chang J, Fu X, Zhang Z, Yan R . Develop a novel superparamagnetic nano-carrier for drug delivery to brain glioma. Drug Deliv. 2013; 20(3-4):95-101. DOI: 10.3109/10717544.2013.779328. View

13.

Pohl U, Cairncross J, Louis D . Homozygous deletions of the CDKN2C/p18INK4C gene on the short arm of chromosome 1 in anaplastic oligodendrogliomas. Brain Pathol. 1999; 9(4):639-43. PMC: 8098363. DOI: 10.1111/j.1750-3639.1999.tb00545.x. View

14.

Losman J, Kaelin Jr W . What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 2013; 27(8):836-52. PMC: 3650222. DOI: 10.1101/gad.217406.113. View

15.

Wu W, Li H, Wang Z, Dai Z, Liang X, Luo P . The tertiary lymphoid structure-related signature identified PTGDS in regulating PD-L1 and promoting the proliferation and migration of glioblastoma. Heliyon. 2024; 10(1):e23915. PMC: 10777022. DOI: 10.1016/j.heliyon.2023.e23915. View

16.

Lita A, Pliss A, Kuzmin A, Yamasaki T, Zhang L, Dowdy T . IDH1 mutations induce organelle defects via dysregulated phospholipids. Nat Commun. 2021; 12(1):614. PMC: 7840755. DOI: 10.1038/s41467-020-20752-6. View

17.

Zhu W, Liu X, He J, Chen D, Hunag Y, Zhang Y . Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: a case control study. BMC Cancer. 2011; 11:393. PMC: 3183044. DOI: 10.1186/1471-2407-11-393. View

18.

Molenaar R, Maciejewski J, Wilmink J, van Noorden C . Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene. 2018; 37(15):1949-1960. PMC: 5895605. DOI: 10.1038/s41388-017-0077-z. View

19.

Wajner M, Latini A, Wyse A, Dutra-Filho C . The role of oxidative damage in the neuropathology of organic acidurias: insights from animal studies. J Inherit Metab Dis. 2004; 27(4):427-48. DOI: 10.1023/B:BOLI.0000037353.13085.e2. View

20.

Wang J, Li J, Shen J, Wang C, Yang L, Zhang X . MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma. BMC Cancer. 2012; 12:227. PMC: 3492170. DOI: 10.1186/1471-2407-12-227. View