Construction and analysis of circular RNA molecular regulatory networks in clear cell renal cell carcinoma

Ma,Chuanyu; Qin,Jie; Zhang,Junpeng; Wang,Xingli; Wu,Dongjun; Li,Xiunan

doi:10.3892/mmr.2019.10811

Construction and analysis of circular RNA molecular regulatory networks in clear cell renal cell carcinoma

Authors:
- Chuanyu Ma
- Jie Qin
- Junpeng Zhang
- Xingli Wang
- Dongjun Wu
- Xiunan Li
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Affiliations: Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116600, P.R. China
Published online on: November 11, 2019 https://doi.org/10.3892/mmr.2019.10811
Pages: 141-150
Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Increasing evidence has indicated that circular (circ)RNAs participate in carcinogenesis; however, the specific regulatory mechanisms underlying the effects of circRNAs, microRNAs (miRNAs/miRs) and genes on the development of clear cell renal cell carcinoma (CCRCC) remain unclear. In the present study, RNA microarray data from CCRCC tissues and control samples were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas, in order to identify significantly dysregulated circRNAs, miRNAs and genes. The Cancer‑Specific circRNA Database was used to explore the interactions between miRNAs and circRNAs, whereas TargetScan and miRDB were employed to predict the mRNA targets of miRNAs. Functional enrichment and prognostic analyses were conducted in R. The results revealed that 324 circRNAs were downregulated, whereas 218 circRNAs were upregulated in cancer. In addition, a circRNA‑miRNA‑mRNA interaction network was constructed. Gene Ontology analysis of the upregulated genes revealed that these genes were enriched in biological processes, including ‘flavonoid metabolic process’, ‘cellular glucuronidation’ and ‘T cell activation’. The downregulated genes were mainly enriched in biological processes, such as ‘nephron development’, ‘kidney development’ and ‘renal system development’. The hub genes, including membrane palmitoylated protein 7, aldehyde dehydrogenase 6 family member A1, transcription factor AP‑2α, collagen type IV α 4 chain, nuclear receptor subfamily 3 group C member 2, plasminogen, Holliday junction recognition protein, claudin 10, kinesin family member 18B and thyroid hormone receptor β, and the hub miRNAs, including miR‑21‑3p, miR‑155‑3p, miR‑144‑3p, miR‑142‑5p, miR‑875‑3p, miR‑885‑3p, miR‑3941, miR‑224‑3p, miR‑584‑3p and miR‑138‑1‑3p, were significantly associated with CCRCC survival. In conclusion, these results suggested that the significantly dysregulated circRNAs, miRNAs and genes identified in this study may be considered potential biomarkers of the carcinogenesis of CCRCC and the survival of patients with this disease.

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1	Schmidt LS and Linehan WM: Genetic predisposition to kidney cancer. Semin Oncol. 43:566–574. 2016. View Article : Google Scholar : PubMed/NCBI
2	Morris MR and Latif F: The epigenetic landscape of renal cancer. Nat Rev Nephrol. 13:47–60. 2017. View Article : Google Scholar : PubMed/NCBI
3	Moch H, Srigley J, Delahunt B, Montironi R, Egevad L and Tan PH: Biomarkers in renal cancer. Virchows Arch. 464:359–365. 2014. View Article : Google Scholar : PubMed/NCBI
4	Dabestani S, Marconi L and Bex A: Metastasis therapies for renal cancer. Curr Opin Urol. 26:566–572. 2016. View Article : Google Scholar : PubMed/NCBI
5	Lu CH, Ou YC, Huang LH, Weng WC, Chang YK, Chen HL, Hsu CY and Tung MC: Early dutasteride monotherapy in patients with elevated serum prostate-specific antigen levels following robot-assisted radical prostatectomy. Front Oncol. 9:6912019. View Article : Google Scholar : PubMed/NCBI
6	Corgna E, Betti M, Gatta G, Roila F and De Mulder PH: Renal cancer. Crit Rev Oncol Hematol. 64:247–262. 2007. View Article : Google Scholar : PubMed/NCBI
7	Zhao ZJ and Shen J: Circular RNA participates in the carcinogenesis and the malignant behavior of cancer. RNA Biol. 14:514–521. 2017. View Article : Google Scholar : PubMed/NCBI
8	Salzman J: Circular RNA expression: Its potential regulation and function. Trends Genet. 32:309–316. 2016. View Article : Google Scholar : PubMed/NCBI
9	Meng X, Li X, Zhang P, Wang J, Zhou Y and Chen M: Circular RNA: An emerging key player in RNA world. Brief Bioinform. 18:547–557. 2017.PubMed/NCBI
10	Zhang HD, Jiang LH, Sun DW, Hou JC and Ji ZL: CircRNA: A novel type of biomarker for cancer. Breast Cancer. 25:1–7. 2018. View Article : Google Scholar : PubMed/NCBI
11	Ebbesen KK, Hansen TB and Kjems J: Insights into circular RNA biology. RNA Biol. 14:1035–1045. 2017. View Article : Google Scholar : PubMed/NCBI
12	Wang K, Sun Y, Tao W, Fei X and Chang C: Androgen receptor (AR) promotes clear cell renal cell carcinoma (ccRCC) migration and invasion via altering the circHIAT1/miR-195-5p/29a-3p/29c-3p/CDC42 signals. Cancer Lett. 394:1–12. 2017. View Article : Google Scholar : PubMed/NCBI
13	Wang G, Xue W, Jian W, Liu P, Wang Z, Wang C, Li H, Yu Y, Zhang D and Zhang C: The effect of Hsa_circ_0001451 in clear cell renal cell carcinoma cells and its relationship with clinicopathological features. J Cancer. 9:3269–3277. 2018. View Article : Google Scholar : PubMed/NCBI
14	Xiong Y, Zhang J and Song C: CircRNA ZNF609 functions as a competitive endogenous RNA to regulate FOXP4 expression by sponging miR-138-5p in renal carcinoma. J Cell Physiol. 234:10646–10654. 2019. View Article : Google Scholar : PubMed/NCBI
15	Xia S, Feng J, Chen K, Ma Y, Gong J, Cai F, Jin Y, Gao Y, Xia L, Chang H, et al: CSCD: A database for cancer-specific circular RNAs. Nucleic Acids Res. 46:D925–D929. 2018. View Article : Google Scholar : PubMed/NCBI
16	The Gene Ontology (GO) project in 2006. Nucleic Acids Res. 34:D322–D326. 2006. View Article : Google Scholar : PubMed/NCBI
17	Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI
18	Sanchez-Mejias A and Tay Y: Competing endogenous RNA networks: Tying the essential knots for cancer biology and therapeutics. J Hematol Oncol. 8:302015. View Article : Google Scholar : PubMed/NCBI
19	D'Uva G and Lauriola M: Towards the emerging crosstalk: ERBB family and steroid hormones. Semin Cell Dev Biol. 50:143–152. 2016. View Article : Google Scholar : PubMed/NCBI
20	Huynh TP, Barwe SP, Lee SJ, McSpadden R, Franco OE, Hayward SW, Damoiseaux R, Grubbs SS, Petrelli NJ and Rajasekaran AK: Glucocorticoids suppress renal cell carcinoma progression by enhancing Na,K-ATPase beta-1 subunit expression. PLoS One. 10:e01224422015. View Article : Google Scholar : PubMed/NCBI
21	Feldman RD, Ding Q, Hussain Y, Limbird LE, Pickering JG and Gros R: Aldosterone mediates metastatic spread of renal cancer via the G protein-coupled estrogen receptor (GPER). FASEB J. 30:2086–2096. 2016. View Article : Google Scholar : PubMed/NCBI
22	Zhong X, Drgonova J, Li CY and Uhl GR: Human cell adhesion molecules: Annotated functional subtypes and overrepresentation of addiction-associated genes. Ann N Y Acad Sci. 1349:83–95. 2015. View Article : Google Scholar : PubMed/NCBI
23	Nagata M, Sakurai-Yageta M, Yamada D, Goto A, Ito A, Fukuhara H, Kume H, Morikawa T, Fukayama M, Homma Y and Murakami Y: Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma. Int J Cancer. 130:1329–1337. 2012. View Article : Google Scholar : PubMed/NCBI
24	He W, Li X, Xu S, Ai J, Gong Y, Gregg JL, Guan R, Qiu W, Xin D, Gingrich JR, et al: Aberrant methylation and loss of CADM2 tumor suppressor expression is associated with human renal cell carcinoma tumor progression. Biochem Biophys Res Commun. 435:526–532. 2013. View Article : Google Scholar : PubMed/NCBI
25	Dalgin GS, Drever M, Williams T, King T, DeLisi C and Liou LS: Identification of novel epigenetic markers for clear cell renal cell carcinoma. J Urol. 180:1126–1130. 2008. View Article : Google Scholar : PubMed/NCBI
26	Zhao Z, Zhang M, Duan X, Deng T, Qiu H and Zeng G: Low NR3C2 levels correlate with aggressive features and poor prognosis in non-distant metastatic clear-cell renal cell carcinoma. J Cell Physiol. 233:6825–6838. 2018. View Article : Google Scholar : PubMed/NCBI
27	Nouhaud FX, Blanchard F, Sesboue R, Flaman JM, Sabourin JC, Pfister C and Di Fiore F: Clinical relevance of gene copy number variation in metastatic clear cell renal cell carcinoma. Clin Genitourin Cancer. 16:e795–e805. 2018. View Article : Google Scholar : PubMed/NCBI
28	An F, Liu Y and Hu Y: miR-21 inhibition of LATS1 promotes proliferation and metastasis of renal cancer cells and tumor stem cell phenotype. Oncol Lett. 14:4684–4688. 2017. View Article : Google Scholar : PubMed/NCBI
29	Bera A, Ghosh-Choudhury N, Dey N, Das F, Kasinath BS, Abboud HE and Choudhury GG: NFκB-mediated cyclin D1 expression by microRNA-21 influences renal cancer cell proliferation. Cell Signal. 25:2575–2586. 2013. View Article : Google Scholar : PubMed/NCBI
30	Yuan H, Xin S, Huang Y, Bao Y, Jiang H, Zhou L, Ren X, Li L, Wang Q and Zhang J: Downregulation of PDCD4 by miR-21 suppresses tumor transformation and proliferation in a nude mouse renal cancer model. Oncol Lett. 14:3371–3378. 2017. View Article : Google Scholar : PubMed/NCBI
31	Gao Y, Ma X, Yao Y, Li H, Fan Y, Zhang Y, Zhao C, Wang L, Ma M, Lei Z and Zhang X: miR-155 regulates the proliferation and invasion of clear cell renal cell carcinoma cells by targeting E2F2. Oncotarget. 7:20324–20337. 2016.PubMed/NCBI
32	Wei RJ, Zhang CH and Yang WZ: MiR-155 affects renal carcinoma cell proliferation, invasion and apoptosis through regulating GSK-3β/β-catenin signaling pathway. Eur Rev Med Pharmacol Sci. 21:5034–5041. 2017.PubMed/NCBI
33	Xiao W, Lou N, Ruan H, Bao L, Xiong Z, Yuan C, Tong J, Xu G, Zhou Y, Qu Y, et al: Mir-144-3p promotes cell proliferation, metastasis, sunitinib resistance in clear cell renal cell carcinoma by downregulating ARID1A. Cell Physiol Biochem. 43:2420–2433. 2017. View Article : Google Scholar : PubMed/NCBI
34	Lou N, Ruan AM, Qiu B, Bao L, Xu YC, Zhao Y, Sun RL, Zhang ST, Xu GH, Ruan HL, et al: miR-144-3p as a novel plasma diagnostic biomarker for clear cell renal cell carcinoma. Urol Oncol. 35:36.e7–36.e14. 2017. View Article : Google Scholar
35	Salzman J, Chen RE, Olsen MN, Wang PL and Brown PO: Cell-type specific features of circular RNA expression. PLoS Genet. 9:e10037772013. View Article : Google Scholar : PubMed/NCBI
36	Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF and Sharpless NE: Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 19:141–157. 2013. View Article : Google Scholar : PubMed/NCBI
37	Rybak-Wolf A, Stottmeister C, Glažar P, Jens M, Pino N, Giusti S, Hanan M, Behm M, Bartok O, Ashwal-Fluss R, et al: Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell. 58:870–885. 2015. View Article : Google Scholar : PubMed/NCBI
38	Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al: Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 495:333–338. 2013. View Article : Google Scholar : PubMed/NCBI
39	Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, Zhu S, Yang L and Chen LL: Circular intronic long noncoding RNAs. Mol Cell. 51:792–806. 2013. View Article : Google Scholar : PubMed/NCBI