circNRIP1 facilitates keloid progression via FXR1‑mediated upregulation of miR‑503‑3p and miR‑503‑5p

Wang,Baolin; Yin,Hang; Zhang,Hongmei; Wang,Tiantian

doi:10.3892/ijmm.2021.4903

circNRIP1 facilitates keloid progression via FXR1‑mediated upregulation of miR‑503‑3p and miR‑503‑5p

Authors:
- Baolin Wang
- Hang Yin
- Hongmei Zhang
- Tiantian Wang
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Affiliations: Department of Dermatology, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277100, P.R. China, Department of Neurosurgery, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277100, P.R. China, Department of Pharmacy, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277100, P.R. China
Published online on: March 1, 2021 https://doi.org/10.3892/ijmm.2021.4903
Article Number: 70
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Circular nuclear receptor interacting protein 1 (circNRIP1) is implicated in tumor initiation and progression; however, the underlying mechanism of keloid progression is unclear. To the best of our knowledge, the present study is the first to characterize the contribution of circNRIP1 to keloid progression and evaluate the potential underlying molecular mechanisms using keloid‑derived fibroblasts. The expression profile of circNRIP1 was confirmed in keloid tissue. The contribution of circNRIP1 to keloid progression was investigated via loss‑of‑function assays. Furthermore, the molecular mechanism by which circNRIP1 contributes to pre‑microRNA (miR)‑503 maturation through blocking Fbxo4‑mediated Fragile‑X mental retardation 1 (FXR1) ubiquitination was verified. Finally, the biological functions of FXR1, miR‑503‑3p, and miR‑503‑5p in keloid‑derived fibroblast proliferation, apoptosis and extracellular matrix accumulation were confirmed. circNRIP1 was highly expressed in keloid tissue and keloid‑derived fibroblasts. Functional analysis showed that circNRIP1 knockdown successfully blocked the proliferation and expression of extracellular matrix‑associated proteins while increasing the rate of apoptosis in keloid‑derived fibroblasts. Mechanistically, circNRIP1 maintained FXR1 stability by impeding Fbxo4‑mediated FXR1 ubiquitination and degradation. Additionally, FXR1 increased the abundance of miR‑503‑3p and miR‑503‑5p by contributing to pre‑miR‑503 maturation. Knockdown of FXR1, miR‑503‑3p and miR‑503‑5p also inhibited proliferation and extracellular matrix accumulation in keloid‑derived fibroblasts and increased levels of cell apoptosis. Collectively, the present study confirmed that circNRIP1 contributed to pre‑miR‑503 maturation via blocking Fbxo4‑mediated FXR1 ubiquitination and degradation, which facilitates keloid progression. These results indicate that circNRIP1 has potential as a novel therapeutic target for the control and/or treatment of keloids.

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1	Liu T, Ma X, Ouyang T, Chen H, Xiao Y, Huang Y, Liu J and Xu M: Efficacy of 5-aminolevulinic acid-based photodynamic therapy against keloid compromised by downregulation of SIRT1-SIRT3-SOD2-mROS dependent autophagy pathway. Redox Biol. 20:195–203. 2019. View Article : Google Scholar
2	Shi K, Qiu X, Zheng W, Yan D and Peng W: MiR-203 regulates keloid fibroblast proliferation, invasion, and extracellular matrix expression by targeting EGR1 and FGF2. Biomed Pharmacother. 108:1282–1288. 2018. View Article : Google Scholar : PubMed/NCBI
3	Har-Shai Y, Brown W, Labbé D, Dompmartin A, Goldine I, Gil T, Mettanes I and Pallua N: Intralesional cryosurgery for the treatment of hypertrophic scars and keloids following aesthetic surgery: The results of a prospective observational study. Int J Low Extrem Wounds. 7:169–175. 2008. View Article : Google Scholar : PubMed/NCBI
4	Berman B, Maderal A and Raphael B: Keloids and hypertrophic scars: Pathophysiology, classification, and treatment. Dermatol Surg. 43(Suppl 1): S3–S18. 2017. View Article : Google Scholar
5	Yang JY and Yang SY: Are auricular keloids and persistent hypertrophic scars resectable? The role of intrascar excision. Ann Plast Surg. 69:637–642. 2012. View Article : Google Scholar : PubMed/NCBI
6	Shin JY, Yun SK, Roh SG, Lee NH and Yang KM: Efficacy of 2 representative topical agents to prevent keloid recurrence after surgical excision. J Oral Maxillofac Surg. 75:401.e1–401.e6. 2017. View Article : Google Scholar
7	Nong Q, Li S, Wu Y and Liu D: LncRNA COL1A2-AS1 inhibits the scar fibroblasts proliferation via regulating miR-21/Smad7 pathway. Biochem Biophys Res Commun. 495:319–324. 2018. View Article : Google Scholar
8	Yan L, Wang LZ, Xiao R, Cao R, Pan B, Lv XY, Jiao H, Zhuang Q, Sun XJ and Liu YB: Inhibition of microRNA-21-5p reduces keloid fibroblast autophagy and migration by targeting PTEN after electron beam irradiation. Lab Invest. 100:387–399. 2020. View Article : Google Scholar
9	Zhang G, Guan Q, Chen G, Qian F and Liang J: DNA methylation of the CDC2L1 gene promoter region decreases the expression of the CDK11p58 protein and reduces apoptosis in keloid fibroblasts. Arch Dermatol Res. 310:107–115. 2018. View Article : Google Scholar
10	Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB and Kjems J: The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 20:675–691. 2019. View Article : Google Scholar : PubMed/NCBI
11	Yu J, Xu QG, Wang ZG, Yang Y, Zhang L, Ma JZ, Sun SH, Yang F and Zhou WP: Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. J Hepatol. 68:1214–1227. 2018. View Article : Google Scholar : PubMed/NCBI
12	Yao J, Zhang C, Chen Y and Gao S: Downregulation of circular RNA circ-LDLRAD3 suppresses pancreatic cancer progression through miR-137-3p/PTN axis. Life Sci. 239:1168712019. View Article : Google Scholar : PubMed/NCBI
13	Peng Y, Song X, Zheng Y, Cheng H and Lai W: circCOL3A1- 859267 regulates type I collagen expression by sponging miR-29c in human dermal fibroblasts. Eur J Dermatol. 28:613–620. 2018.PubMed/NCBI
14	Shi J, Yao S, Chen P, Yang Y, Qian M, Han Y, Wang N, Zhao Y, He Y, Lyu L and Lu D: The integrative regulatory network of circRNA and microRNA in keloid scarring. Mol Biol Rep. 47:201–209. 2020. View Article : Google Scholar
15	Zhang X, Wang S, Wang H, Cao J, Huang X, Chen Z, Xu P, Sun G, Xu J, Lv J and Xu Z: Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. Mol Cancer. 18:202019. View Article : Google Scholar : PubMed/NCBI
16	Li M, Cai J, Han X and Ren Y: Downregulation of circNRIP1 suppresses the paclitaxel resistance of ovarian cancer via regulating the miR-211-5p/HOXC8 axis. Cancer Manag Res. 12:9159–9171. 2020. View Article : Google Scholar : PubMed/NCBI
17	Xu G, Li M, Wu J, Qin C, Tao Y and He H: Circular RNA circ- NRIP1 sponges microRNA-138-5p to maintain hypoxia-induced resistance to 5-fluorouracil through HIF-1α-dependent glucose metabolism in gastric carcinoma. Cancer Manag Res. 12:2789–2802. 2020. View Article : Google Scholar :
18	Xie R, Tang J, Zhu X and Jiang H: Silencing of hsa_circ_0004771 inhibits proliferation and induces apoptosis in breast cancer through activation of miR-653 by targeting ZEB2 signaling pathway. Biosci Rep. May 17–2019.Epub ahead of print. View Article : Google Scholar
19	Wang L, Tong X, Zhou Z, Wang S, Lei Z, Zhang T, Liu Z, Zeng Y, Li C, Zhao J, et al: Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-β-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ in non-small cell lung cancer. Mol Cancer. 17:1402018. View Article : Google Scholar
20	Zheng X, Chen L, Zhou Y, Wang Q, Zheng Z, Xu B, Wu C, Zhou Q, Hu W, Wu C and Jiang J: A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling. Mol Cancer. 18:472019. View Article : Google Scholar : PubMed/NCBI
21	Huang X, He M, Huang S, Lin R, Zhan M, Yang D, Shen H, Xu S, Cheng W, Yu J, et al: Circular RNA circERBB2 promotes gallbladder cancer progression by regulating PA2G4-dependent rDNA transcription. Mol Cancer. 18:1662019. View Article : Google Scholar : PubMed/NCBI
22	Du WW, Fang L, Yang W, Wu N, Awan FM, Yang Z and Yang BB: Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity. Cell Death Differ. 24:357–370. 2017. View Article : Google Scholar :
23	Liang WC, Wong CW, Liang PP, Shi M, Cao Y, Rao ST, Tsui SK, Waye MM, Zhang Q, Fu WM and Zhang JF: Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol. 20:842019. View Article : Google Scholar
24	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
25	Hartmann P, Zhou Z, Natarelli L, Wei Y, Nazari-Jahantigh M, Zhu M, Grommes J, Steffens S, Weber C and Schober A: Endothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4. Nat Commun. 7:105212016. View Article : Google Scholar : PubMed/NCBI
26	Patop IL, Wüst S and Kadener S: Past, present, and future of circRNAs. EMBO J. 38:e1008362019. View Article : Google Scholar : PubMed/NCBI
27	Wu H, Wu S, Zhu Y, Ye M, Shen J, Liu Y, Zhang Y and Bu S: Hsa_circRNA_0054633 is highly expressed in gestational diabetes mellitus and closely related to glycosylation index. Clin Epigenetics. 11:222019. View Article : Google Scholar : PubMed/NCBI
28	Zhang Z, Yu K, Liu O, Xiong Y, Yang X, Wang S, Zhang S, Feng Y and Peng Y: Expression profile and bioinformatics analyses of circular RNAs in keloid and normal dermal fibroblasts. Exp Cell Res. 388:1117992020. View Article : Google Scholar : PubMed/NCBI
29	Yu J, Yang M, Zhou B, Luo J, Zhang Z, Zhang W and Yan Z: CircRNA-104718 acts as competing endogenous RNA and promotes hepatocellular carcinoma progression through microRNA-218-5p/TXNDC5 signaling pathway. Clin Sci (Lond). 133:1487–1503. 2019. View Article : Google Scholar
30	Chen X, Ouyang Z, Shen Y, Liu B, Zhang Q, Wan L, Yin Z, Zhu W, Li S and Peng D: CircRNA_28313/miR-195a/CSF1 axis modulates osteoclast differentiation to affect OVX-induced bone absorption in mice. RNA Biol. 16:1249–1262. 2019. View Article : Google Scholar : PubMed/NCBI
31	Liu J, Ren J, Su L, Cheng S, Zhou J, Ye X, Dong Y, Sun S, Qi F, Liu Z, et al: Human adipose tissue-derived stem cells inhibit the activity of keloid fibroblasts and fibrosis in a keloid model by paracrine signaling. Burns. 44:370–385. 2018. View Article : Google Scholar
32	Andrews JP, Marttala J, Macarak E, Rosenbloom J and Uitto J: Keloids: The paradigm of skin fibrosis-pathomechanisms and treatment. Matrix Biol. 51:37–46. 2016. View Article : Google Scholar : PubMed/NCBI
33	Jin J, Zhai HF, Jia ZH and Luo XH: Long non-coding RNA HOXA11-AS induces type I collagen synthesis to stimulate keloid formation via sponging miR-124-3p and activation of Smad5 signaling. Am J Physiol Cell Physiol. 317:C1001–C1010. 2019. View Article : Google Scholar : PubMed/NCBI
34	Dong W, Dai ZH, Liu FC, Guo XG, Ge CM, Ding J, Liu H and Yang F: The RNA-binding protein RBM3 promotes cell proliferation in hepatocellular carcinoma by regulating circular RNA SCD-circRNA 2 production. EBioMedicine. 45:155–167. 2019. View Article : Google Scholar : PubMed/NCBI
35	Wang L, Long H, Zheng Q, Bo X, Xiao X and Li B: Circular RNA circRHOT1 promotes hepatocellular carcinoma progression by initiation of NR2F6 expression. Mol Cancer. 18:1192019. View Article : Google Scholar : PubMed/NCBI
36	Sun S, Wang W, Luo X, Li Y, Liu B and Li X, Zhang B, Han S and Li X: Circular RNA circ-ADD3 inhibits hepatocellular carcinoma metastasis through facilitating EZH2 degradation via CDK1-mediated ubiquitination. Am J Cancer Res. 9:1695–1707. 2019.PubMed/NCBI
37	Cao S, Zheng J, Liu X, Liu Y, Ruan X, Ma J, Liu L, Wang D, Yang C, Cai H, et al: FXR1 promotes the malignant biological behavior of glioma cells via stabilizing MIR17HG. J Exp Clin Cancer Res. 38:372019. View Article : Google Scholar : PubMed/NCBI
38	Huang S, Li X, Zheng H, Si X, Li B, Wei G, Li C, Chen Y, Chen Y, Liao W, et al: Loss of super-enhancer-regulated circRNA Nfix induces cardiac regeneration after myocardial infarction in adult mice. Circulation. 139:2857–2876. 2019. View Article : Google Scholar : PubMed/NCBI
39	Zang J, Lu D and Xu A: The interaction of circRNAs and RNA binding proteins: An important part of circRNA maintenance and function. J Neurosci Res. 98:87–97. 2020. View Article : Google Scholar
40	Qie S, Majumder M, Mackiewicz K, Howley BV, Peterson YK, Howe PH, Palanisamy V and Diehl JA: Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma. Nat Commun. 8:15342017. View Article : Google Scholar : PubMed/NCBI
41	Fan Y, Yue J, Xiao M, Han-Zhang H, Wang YV, Ma C, Deng Z, Li Y, Yu Y, Wang X, et al: FXR1 regulates transcription and is required for growth of human cancer cells with TP53/FXR2 homozygous deletion. Elife. 6:e261292017. View Article : Google Scholar :
42	Cao H, Gao R, Yu C, Chen L and Feng Y: The RNA-binding protein FXR1 modulates prostate cancer progression by regulating FBXO4. Funct Integr Genomics. 19:487–496. 2019. View Article : Google Scholar : PubMed/NCBI
43	Majumder M and Palanisamy V: RNA binding protein FXR1-miR301a-3p axis contributes to p21WAF1 degradation in oral cancer. PLoS Genet. 16:e10085802020. View Article : Google Scholar : PubMed/NCBI
44	Xu XL, Zong R, Li Z, Biswas MH, Fang Z, Nelson DL and Gao FB: FXR1P but not FMRP regulates the levels of mammalian brain-specific microRNA-9 and microRNA-124. J Neurosci. 31:13705–13709. 2011. View Article : Google Scholar : PubMed/NCBI
45	Vasudevan S and Steitz JA: AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell. 128:1105–1118. 2007. View Article : Google Scholar : PubMed/NCBI
46	Zhong L, Bian L, Lyu J, Jin H, Liu Z, Lyu L and Lu D: Identification and integrated analysis of microRNA expression profiles in keloid. J Cosmet Dermatol. 17:917–924. 2018. View Article : Google Scholar : PubMed/NCBI
47	Zhao Z, Fan X, Jiang L, Xu Z, Xue L, Zhan Q and Song Y: miR-503-3p promotes epithelial-mesenchymal transition in breast cancer by directly targeting SMAD2 and E-cadherin. J Genet Genomics. 44:75–84. 2017. View Article : Google Scholar : PubMed/NCBI
48	Jiang SP and Li ZR: MiR-503-5p regulates cell epithelial-to-mesenchymal transition, metastasis and prognosis of hepatocellular carcinoma through inhibiting WEE1. Eur Rev Med Pharmacol Sci. 23:2028–2037. 2019.PubMed/NCBI
49	Jee YH, Wang J, Yue S, Jennings M, Clokie SJ, Nilsson O, Lui JC and Baron J: mir-374-5p, mir-379-5p, and mir-503-5p regulate proliferation and hypertrophic differentiation of growth plate chondrocytes in male rats. Endocrinology. 159:1469–1478. 2018. View Article : Google Scholar : PubMed/NCBI
50	Fu Y, Meng Y, Gu X, Tian S, Hou X and Ji M: miR-503 expression is downregulated in cervical cancer and suppresses tumor growth by targeting AKT2. J Cell Biochem. Jan 29–2019.Epub ahead of print. View Article : Google Scholar
51	Cai X, Nie J, Chen L and Yu F: Circ_0000267 promotes gastric cancer progression via sponging MiR-503-5p and regulating HMGA2 expression. Mol Genet Genomic Med. 8:e10932020. View Article : Google Scholar
52	Sun Y, Li L, Xing S, Pan Y, Shi Y, Zhang L and Shen Q: miR-503-3p induces apoptosis of lung cancer cells by regulating p21 and CDK4 expression. Cancer Biomark. 20:597–608. 2017. View Article : Google Scholar : PubMed/NCBI