Downregulation of hsa_circ_0026123 suppresses ovarian cancer cell metastasis and proliferation through the miR‑124‑3p/EZH2 signaling pathway

Yang,Xiaoyun; Wang,Jianjun; Li,Huaifang; Sun,Yi; Tong,Xiaowen

doi:10.3892/ijmm.2020.4804

Downregulation of hsa_circ_0026123 suppresses ovarian cancer cell metastasis and proliferation through the miR‑124‑3p/EZH2 signaling pathway

Authors:
- Xiaoyun Yang
- Jianjun Wang
- Huaifang Li
- Yi Sun
- Xiaowen Tong
View Affiliations

Affiliations: Department of Gynecology and Obstetrics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China, Department of Gynecology and Obstetrics, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, P.R. China
Published online on: December 1, 2020 https://doi.org/10.3892/ijmm.2020.4804
Pages: 668-676
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Circular RNAs (circRNAs) play a role in various types of cancer. The present study suggested that hsa_circ_0026123 expression was upregulated in ovarian cancer (OVA), which was associated with its role in OVA. However, the role of hsa_circ_0026123 in OVA cell invasion and proliferation remains unclear. In the present study, OVA tissues and cell lines were used to investigate the functions of hsa_circ_0026123. The associations between hsa_circ_0026123, miR‑124‑3p and enhancer of zeste homolog 2 (EZH2) were examined using a luciferase reporter assay. RT‑qPCR and western blot analysis were used for gene and protein expression analysis, respectively. Tumor growth was detected using nude mouse tumor xenografts derived from SKOV3 cells, with or without hsa_circ_0026123 downregulation. The results confirmed that hsa_circ_0026123 expression was upregulated in OVA tissues and cell lines, while hsa_circ_0026123 silencing suppressed cell proliferation and migration; it also suppressed the expression of cancer stem cell (CSC) differentiation‑related markers in either in vivo or in vitro experiments. The data revealed that hsa_circ_0026123 downregulation suppressed EZH2 expression by miR‑124‑3p ‘sponging’, which was confirmed by rescue experiments and luciferase reporter assays. The results revealed that hsa_circ_0026123 silencing suppressed ovarian cancer cell progression via the miR‑124‑3p/EZH2 signaling pathway. Overall, the findings demonstrated that hsa_circ_0026123 knockdown inhibited OVA cell progression by regulating the miR‑124‑3p/EZH2 axis. This methodology may thus be used for the targeted therapy of OVA, as well as a candidate biomarker for the diagnosis and treatment of OVA.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Rustin G, van der Burg M, Griffin C, Qian W and Swart AM: Early versus delayed treatment of relapsed ovarian cancer. Lancet. 377:380–381. 2011. View Article : Google Scholar : PubMed/NCBI
3	Doubeni CA, Doubeni AR and Myers AE: Diagnosis and management of ovarian cancer. Am Fam Physician. 93:937–944. 2016.PubMed/NCBI
4	Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, Chen D, Gu J, He X and Huang S: Circular RNA is enriched and stable in exosomes: A promising biomarker for cancer diagnosis. Cell Res. 25:981–984. 2015. View Article : Google Scholar : PubMed/NCBI
5	Zhang SJ, Chen X, Li CP, Li XM, Liu C, Liu BH, Shan K, Jiang Q, Zhao C and Yan B: Identification and characterization of circular RNAs as a new class of putative biomarkers in diabetes retinopathy. Invest Ophthalmol Vis Sci. 58:6500–6509. 2017. View Article : Google Scholar : PubMed/NCBI
6	Wilusz JE and Sharp PA: Molecular biology. A circuitous route to noncoding RNA. Science. 340:440–441. 2013. View Article : Google Scholar : PubMed/NCBI
7	Kumar L, Shamsuzzama, Haque R, Baghel T and Nazir A: Circular RNAs: The emerging class of non-coding RNAs and their potential role in human neurodegenerative diseases. Mol Neurobiol. 54:7224–7234. 2017. View Article : Google Scholar
8	Piwecka M, Glazar P, Hernandez-Miranda LR, Memczak S, Wolf SA, Rybak-Wolf A, Filipchyk A, Klironomos F, Jara CAC, Fenske P, et al: Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science. 357:eaam85262017. View Article : Google Scholar : PubMed/NCBI
9	Shan K, Liu C, Liu BH, Chen X, Dong R, Liu X, Zhang YY, Liu B, Zhang SJ, Wang JJ, et al: Circular noncoding RNA HIPK3 mediates retinal vascular dysfunction in diabetes mellitus. Circulation. 136:1629–1642. 2017. View Article : Google Scholar : PubMed/NCBI
10	Hsiao KY, Lin YC, Gupta SK, Chang N, Yen L, Sun HS and Tsai SJ: Noncoding effects of circular RNA CCDC66 promote colon cancer growth and metastasis. Cancer Res. 77:2339–2350. 2017. View Article : Google Scholar : PubMed/NCBI
11	Guo Q, He Y, Sun L, Kong C, Cheng Y and Zhang G: In silico detection of potential prognostic circRNAs through a re-annotation strategy in ovarian cancer. Oncol Lett. 17:3677–3686. 2019.PubMed/NCBI
12	Xiong DD, Dang YW, Lin P, Wen DY, He RQ, Luo DZ, Feng ZB and Chen G: A circRNA-miRNA-mRNA network identification for exploring underlying pathogenesis and therapy strategy of hepatocellular carcinoma. J Transl Med. 16:2202018. View Article : Google Scholar : PubMed/NCBI
13	Guan YJ, Ma JY and Song W: Identification of circRNA-miRNA-mRNA regulatory network in gastric cancer by analysis of microarray data. Cancer Cell Int. 19:1832019. View Article : Google Scholar : PubMed/NCBI
14	Zhang L, Zhou Q, Qiu Q, Hou L, Wu M, Li J, Li X, Lu B, Cheng X, Liu P, et al: CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer. Mol Cancer. 18:1442019. View Article : Google Scholar : PubMed/NCBI
15	Gao Y, Zhang C, Liu Y and Wang M: Circular RNA profiling reveals circRNA1656 as a novel biomarker in high grade serous ovarian cancer. Biosci Trends. 13:204–211. 2019. View Article : Google Scholar : PubMed/NCBI
16	Sheng M, Wei N, Yang HY, Yan M, Zhao QX and Jing LJ: CircRNA UBAP2 promotes the progression of ovarian cancer by sponging microRNA-144. Eur Rev Med Pharmacol Sci. 23:7283–7294. 2019.PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
18	Li J, Yang J, Zhou P, Le Y, Zhou C, Wang S, Xu D, Lin HK and Gong Z: Circular RNAs in cancer: Novel insights into origins, properties, functions and implications. Am J Cancer Res. 5:472–480. 2015.PubMed/NCBI
19	Liu J, Song S, Lin S, Zhang M, Du Y, Zhang D, Xu W and Wang H: Circ-SERPINE2 promotes the development of gastric carcinoma by sponging miR-375 and modulating YWHAZ. Cell Prolif. 52:e126482019. View Article : Google Scholar : PubMed/NCBI
20	Liu G, Shi H, Deng L, Zheng H, Kong W, Wen X and Bi H: Circular RNA circ-FOXM1 facilitates cell progression as ceRNA to target PPDPF and MACC1 by sponging miR-1304-5p in non-small cell lung cancer. Biochem Biophys Res Commun. 513:207–212. 2019. View Article : Google Scholar : PubMed/NCBI
21	Liu C, Zhang H and Liu H: Long noncoding RNA UCA1 accelerates nasopharyngeal carcinoma cell progression by modulating miR-124-3p/ITGB1 axis. Onco Targets Ther. 12:8455–8466. 2019. View Article : Google Scholar : PubMed/NCBI
22	Fu W, Wu X, Yang Z and Mi H: The effect of miR-124-3p on cell proliferation and apoptosis in bladder cancer by targeting EDNRB. Arch Med Sci. 15:1154–1162. 2019. View Article : Google Scholar : PubMed/NCBI
23	Cui RJ, Fan JL, Lin YC, Pan YJ, Liu C, Wan JH, Wang W, Jiang ZY, Zheng XL, Tang JB and Yu XG: miR-124-3p avail-ability is antagonized by LncRNA-MALAT1 for Slug-induced tumor metastasis in hepatocellular carcinoma. Cancer Med. 8:6358–6369. 2019. View Article : Google Scholar : PubMed/NCBI
24	Lv Y, Chen S, Wu J, Lin R, Zhou L, Chen G, Chen H and Ke Y: Upregulation of long non-coding RNA OGFRP1 facilitates endometrial cancer by regulating miR-124-3p/SIRT1 axis and by activating PI3K/AKT/GSK-3β pathway. Artif Cells Nanomed Biotechnol. 47:2083–2090. 2019. View Article : Google Scholar : PubMed/NCBI
25	Zeng B, Zhang X, Zhao J, Wei Z, Zhu H, Fu M, Zou D, Feng Y, Luo H and Lei Y: The role of DNMT1/hsa-miR-124-3p/BCAT1 pathway in regulating growth and invasion of esophageal squamous cell carcinoma. BMC Cancer. 19:6092019. View Article : Google Scholar : PubMed/NCBI
26	Zhao M, Hu X, Xu Y, Wu C, Chen J, Ren Y, Kong L, Sun S, Zhang L, Jin R and Zhou X: Targeting of EZH2 inhibits epithelialmesenchymal transition in head and neck squamous cell carcinoma via regulating the STAT3/VEGFR2 axis. Int J Oncol. 55:1165–1175. 2019.PubMed/NCBI
27	Nishimoto S, Hamajima Y, Toda Y, Toyoda H, Kitamura K and Komurasaki T: Identification of a novel smooth muscle associated protein, smap2, upregulated during neointima formation in a rat carotid endarterectomy model. Biochim Biophys Acta. 1576:225–230. 2002. View Article : Google Scholar : PubMed/NCBI
28	Maier S, Paulsson M and Hartmann U: The widely expressed extracellular matrix protein SMOC-2 promotes keratinocyte attachment and migration. Exp Cell Res. 314:2477–2487. 2008. View Article : Google Scholar : PubMed/NCBI
29	Liu H, Sun Q, Sun Y, Zhang J, Yuan H, Pang S, Qi X, Wang H, Zhang M, Zhang H, et al: MELK and EZH2 cooperate to regulate medulloblastoma cancer stem-like cell proliferation and differentiation. Mol Cancer Res. 15:1275–1286. 2017. View Article : Google Scholar : PubMed/NCBI
30	Chen JF, Luo X, Xiang LS, Li HT, Zha L, Li N, He JM, Xie GF, Xie X and Liang HJ: EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/β-catenin signaling. Oncotarget. 7:41540–41558. 2016. View Article : Google Scholar : PubMed/NCBI
31	Karami Madani G, Rad A, Molavi M, Ardalan Khales S, Abbaszadegan MR and Forghanifard MM: Predicting the correlation of EZH2 and cancer stem cell markers in esophageal squamous cell carcinoma. J Gastrointest Cancer. 49:437–441. 2018. View Article : Google Scholar
32	Zhang H, Qi J, Reyes JM, Li L, Rao PK, Li F, Lin CY, Perry JA, Lawlor MA, Federation A, et al: Oncogenic deregulation of EZH2 as an opportunity for targeted therapy in lung cancer. Cancer Discov. 6:1006–1021. 2016. View Article : Google Scholar : PubMed/NCBI
33	Stazi G, Zwergel C, Mai A and Valente S: EZH2 inhibitors: A patent review (2014-2016). Expert Opin Ther Pat. 27:797–813. 2017. View Article : Google Scholar : PubMed/NCBI