MiR-18a-downregulated RORA Inhibits the Proliferation and Tumorigenesis of Glioma Using the TNF-α-mediated NF-κB Signaling Pathway

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2020 Feb 17

PMID 32062354

Citations 36

Authors

Yang Jiang

Jinpeng Zhou

JunShuang Zhao

Dianqi Hou

Haiying Zhang

Long Li

Dan Zou

Jiangfeng Hu

Ye Zhang

Zhitao Jing

Affiliations

Soon will be listed here.

Abstract

Background: Glioma has a poor prognosis, and is the most common primary and lethal primary malignant tumor in the central nervous system. Retinoic acid receptor-related orphan receptor A (RORA) is a member of the ROR subfamily of orphan receptors and plays an anti-tumor role in several cancers.

Methods: A cell viability assay, the Edu assay, neurosphere formation assay, and xenograft experiments were used to detect the proliferative abilities of glioma cell line, glioma stem cells (GSCs). Western blotting, ELISAs, and luciferase reporter assays were used to detect the presence of possible microRNAs.

Findings: Our study found for the first time that RORA was expressed at low levels in gliomas, and was associated with a good prognosis. RORA overexpression inhibited the proliferation and tumorigenesis of glioma cell lines and GSCs via inhibiting the TNF-α mediated NF-κB signaling pathway. In addition, microRNA-18a had a promoting effect on gliomas, and was the possible reason for low RORA expression in gliomas.

Interpretation: RORA may be a promising therapeutic target in the treatment of gliomas.

Citing Articles

The Common Hallmarks and Interconnected Pathways of Aging, Circadian Rhythms, and Cancer: Implications for Therapeutic Strategies.

Wang J, Shao F, Yu Q, Ye L, Wusiman D, Wu R Research (Wash D C). 2025; 8:0612.

PMID: 40046513 PMC: 11880593. DOI: 10.34133/research.0612.

Circadian genes and non-coding RNAs: interactions and implications in cancer.

Yoon G, Roh J, Jang W, Kim W Anim Cells Syst (Seoul). 2025; 29(1):135-148.

PMID: 39944901 PMC: 11816739. DOI: 10.1080/19768354.2025.2459622.

DNMT1-driven methylation of RORA facilitates esophageal squamous cell carcinoma progression under hypoxia through SLC2A3.

Yao W, Shang L, Wang Y, Xu L, Bai Y, Feng M J Transl Med. 2024; 22(1):1167.

PMID: 39741267 PMC: 11686977. DOI: 10.1186/s12967-024-05960-8.

UBR5 metabolically reprograms nasopharyngeal carcinoma cells to promote glycolysis and M2 polarization via SPLUNC1 signaling.

Liu H, Li Y, Tang L, Sun X, Xie W, Xiao T NPJ Precis Oncol. 2024; 8(1):252.

PMID: 39501021 PMC: 11538528. DOI: 10.1038/s41698-024-00747-y.

Tumoral periprostatic adipose tissue exovesicles-derived miR-20a-5p regulates prostate cancer cell proliferation and inflammation through the RORA gene.

Sanchez-Martin S, Altuna-Coy A, Arreaza-Gil V, Bernal-Escote X, Fontgivell J, Ascaso-Til H J Transl Med. 2024; 22(1):661.

PMID: 39010137 PMC: 11251289. DOI: 10.1186/s12967-024-05458-3.

References

Jiang Y, Song Y, Wang R, Hu T, Zhang D, Wang Z . NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells. Cancer Res. 2019; 79(10):2593-2603. DOI: 10.1158/0008-5472.CAN-18-3297. View

Guo X, Qiu W, Liu Q, Qian M, Wang S, Zhang Z . Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways. Oncogene. 2018; 37(31):4239-4259. DOI: 10.1038/s41388-018-0261-9. View

Li B, Wang Y, Xu Y, Liu H, Bloomer W, Zhu D . Genetic variants in RORA and DNMT1 associated with cutaneous melanoma survival. Int J Cancer. 2018; 142(11):2303-2312. PMC: 5893376. DOI: 10.1002/ijc.31243. View

Kojetin D, Burris T . REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov. 2014; 13(3):197-216. PMC: 4865262. DOI: 10.1038/nrd4100. View

Moharrami N, Bjorkoy Tande E, Ryan L, Espevik T, Boyartchuk V . RORα controls inflammatory state of human macrophages. PLoS One. 2018; 13(11):e0207374. PMC: 6261595. DOI: 10.1371/journal.pone.0207374. View

Rajesh Y, Pal I, Banik P, Chakraborty S, Borkar S, Dey G . Insights into molecular therapy of glioma: current challenges and next generation blueprint. Acta Pharmacol Sin. 2017; 38(5):591-613. PMC: 5457688. DOI: 10.1038/aps.2016.167. View

Moraitis A, Giguere V . Transition from monomeric to homodimeric DNA binding by nuclear receptors: identification of RevErbAalpha determinants required for RORalpha homodimer complex formation. Mol Endocrinol. 1999; 13(3):431-9. DOI: 10.1210/mend.13.3.0250. View

Srividya G, Angayarkanni N, Iyer G, Srinivasan B, Agarwal S . Altered retinoid metabolism gene expression in chronic Stevens-Johnson syndrome. Br J Ophthalmol. 2019; 103(8):1015-1023. DOI: 10.1136/bjophthalmol-2018-312849. View

Fu R, Qiu C, Chen H, Zhang Z, Lu M . Retinoic acid receptor-related receptor alpha (RORalpha) is a prognostic marker for hepatocellular carcinoma. Tumour Biol. 2014; 35(8):7603-10. DOI: 10.1007/s13277-014-2007-9. View

10.

Migita H, Satozawa N, Lin J, Morser J, Kawai K . RORalpha1 and RORalpha4 suppress TNF-alpha-induced VCAM-1 and ICAM-1 expression in human endothelial cells. FEBS Lett. 2004; 557(1-3):269-74. DOI: 10.1016/s0014-5793(03)01502-3. View

11.

Paugh B, Bryan L, Paugh S, Wilczynska K, Alvarez S, Singh S . Interleukin-1 regulates the expression of sphingosine kinase 1 in glioblastoma cells. J Biol Chem. 2008; 284(6):3408-17. PMC: 2635028. DOI: 10.1074/jbc.M807170200. View

12.

Ramaswamy P, Goswami K, Dalavaikodihalli Nanjaiah N, Srinivas D, Prasad C . TNF-α mediated MEK-ERK signaling in invasion with putative network involving NF-κB and STAT-6: a new perspective in glioma. Cell Biol Int. 2019; 43(11):1257-1266. DOI: 10.1002/cbin.11125. View

13.

Hu Y, Smyth G . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009; 347(1-2):70-8. DOI: 10.1016/j.jim.2009.06.008. View

14.

Giguere V, Tini M, Flock G, Ong E, Evans R, Otulakowski G . Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 1994; 8(5):538-53. DOI: 10.1101/gad.8.5.538. View

15.

Reynes G, Vila V, Martin M, Parada A, Fleitas T, Reganon E . Circulating markers of angiogenesis, inflammation, and coagulation in patients with glioblastoma. J Neurooncol. 2010; 102(1):35-41. DOI: 10.1007/s11060-010-0290-x. View

16.

Han L, Huang C, Zhang S . The RNA-binding protein SORBS2 suppresses hepatocellular carcinoma tumourigenesis and metastasis by stabilizing RORA mRNA. Liver Int. 2019; 39(11):2190-2203. DOI: 10.1111/liv.14202. View

17.

Qiu M, Chen Y, Jin S, Fang X, He X, Xiong Z . Research on circadian clock genes in non-small-cell lung carcinoma. Chronobiol Int. 2019; 36(6):739-750. DOI: 10.1080/07420528.2018.1509080. View

18.

Calabro M, Mandelli L, Crisafulli C, Lee S, Jun T, Wang S . Neuroplasticity, Neurotransmission and Brain-Related Genes in Major Depression and Bipolar Disorder: Focus on Treatment Outcomes in an Asiatic Sample. Adv Ther. 2018; 35(10):1656-1670. PMC: 6182627. DOI: 10.1007/s12325-018-0781-2. View

19.

Yamamoto T, Mencarelli M, Di Marco C, Mucciolo M, Vascotto M, Balestri P . Overlapping microdeletions involving 15q22.2 narrow the critical region for intellectual disability to NARG2 and RORA. Eur J Med Genet. 2014; 57(4):163-8. DOI: 10.1016/j.ejmg.2014.02.001. View

20.

Li W, Ma S, Bai X, Pan W, Ai L, Tan W . Long noncoding RNA WDFY3-AS2 suppresses tumor progression by acting as a competing endogenous RNA of microRNA-18a in ovarian cancer. J Cell Physiol. 2019; 235(2):1141-1154. DOI: 10.1002/jcp.29028. View