lncRNAPCAT29 inhibits pulmonary fibrosis via the TGF‑β1‑regulated RASAL1/ERK1/2 signal pathway

Liu,Xiaoming; Gao,Shanyu; Xu,Huile

doi:10.3892/mmr.2018.8807

lncRNAPCAT29 inhibits pulmonary fibrosis via the TGF‑β1‑regulated RASAL1/ERK1/2 signal pathway

Authors:
- Xiaoming Liu
- Shanyu Gao
- Huile Xu
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Affiliations: Department of Health Care, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China, Department of Anorectal Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China, Department of Traditional Chinese Medicine, Shandong Provincial Coal Linyi Hot Springs Sanatorium Hospital, Linyi, Shandong 276032, P.R. China
Published online on: March 28, 2018 https://doi.org/10.3892/mmr.2018.8807
Pages: 7781-7788

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Abstract

Pulmonary fibrosis is a severe respiratory disease characterized by the aggregation of extracellular matrix components and inflammation‑associated injury. Studies have suggested that long non‑coding RNAs (lncRNA) may serve a role in the pathophysiological processes of pulmonary fibrosis. However, the potential molecular mechanisms involving the lncRNA, prostate cancer‑associated transcript 29 (lncRNAPCAT29) in the progression of pulmonary fibrosis are yet to be determined. In the present study, the role of lncRNAPCAT29 and the potential signaling mechanism in pulmonary fibrosis progression was investigated. Reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry revealed that the expression levels of lncRNAPCAT29 were downregulated within interstitial lung cells from mice with silica‑induced pulmonary fibrosis. Transfection with lncRNAPCAT29 was associated with upregulated expression of microRNA (miRNA)‑221 and downregulated expression of transforming growth factor‑β1 (TGF‑β1); reduced inflammation and fibrotic progression was also associated with lncRNAPCAT29 transfection. TGF‑β1 expression levels were inhibited within pulmonary fibroblasts due to lncRNAPCAT29 expression; NEDD4 binding protein 2 and Plexin‑A4 expression levels were also suppressed. Analysis of the potential mechanism underlying silica‑induced pulmonary fibrosis revealed that the expression levels of RAS protein activator like 1 (RASAL1) and extracellular signal‑regulated kinases 1/2 (ERK1/2) were suppressed due to lncRNAPCAT29 expression. The results of the present study demonstrated that lncRNAPCAT29 induced miRNA‑221 upregulation and TGF‑β1 downregulation. These observations were associated with reduced inflammation and progression of silica‑induced pulmonary fibrosis via the TGF‑β1‑regulated RASAL1/ERK1/2 signaling pathway, which may serve as a potential target for the treatment of pulmonary fibrosis.

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1	Vaidya S, Hibbert CL, Kinter E and Boes S: Identification of key cost generating events for idiopathic pulmonary fibrosis: A systematic review. Lung. 195:1–8. 2017. View Article : Google Scholar : PubMed/NCBI
2	Renzoni E, Srihari V and Sestini P: Pathogenesis of idiopathic pulmonary fibrosis: Review of recent findings. F1000prime Rep. 6:692014. View Article : Google Scholar : PubMed/NCBI
3	Rozanski C and Mura M: Multi-dimensional indices to stage idiopathic pulmonary fibrosis: A systematic review. Sarcoidosis Vasc Diffuse Lung Dis. 31:8–18. 2014.PubMed/NCBI
4	Upala S and Sanguankeo A: Severity of breathing disorder during sleep is not correlated with idiopathic pulmonary fibrosis: A systematic review and meta-analysis. QJM. 109:1412016. View Article : Google Scholar : PubMed/NCBI
5	Koerner-Rettberg C and Ballmann M: Colistimethate sodium for the treatment of chronic pulmonary infection in cystic fibrosis: An evidence-based review of its place in therapy. Core Evid. 9:99–112. 2014. View Article : Google Scholar : PubMed/NCBI
6	Figueroa T, Boumart I, Coupeau D and Rasschaert D: Hyperediting by ADAR1 of a new herpesvirus lncRNA during the lytic phase of the oncogenic Marek's disease virus. J Gen Virol. 97:2973–2988. 2016. View Article : Google Scholar : PubMed/NCBI
7	Huarte M: RNA. A lncRNA links genomic variation with celiac disease. Science. 352:43–44. 2016. View Article : Google Scholar : PubMed/NCBI
8	Cabianca DS, Casa V and Gabellini D: A novel molecular mechanism in human genetic disease: A DNA repeat-derived lncRNA. RNA Biol. 9:1211–1217. 2012. View Article : Google Scholar : PubMed/NCBI
9	Song X, Cao G, Jing L, Lin S, Wang X, Zhang J, Wang M, Liu W and Lv C: Analysing the relationship between lncRNA and protein-coding gene and the role of lncRNA as ceRNA in pulmonary fibrosis. J Cell Mol Med. 18:991–1003. 2014. View Article : Google Scholar : PubMed/NCBI
10	Wu Q, Han L, Yan W, Ji X, Han R, Yang J, Yuan J and Ni C: miR-489 inhibits silica-induced pulmonary fibrosis by targeting MyD88 and Smad3 and is negatively regulated by lncRNA CHRF. Sci Rep. 6:309212016. View Article : Google Scholar : PubMed/NCBI
11	Sakurai K, Reon BJ, Anaya J and Dutta A: The lncRNA DRAIC/PCAT29 locus constitutes a tumor-suppressive nexus. Mol Cancer Res. 13:828–838. 2015. View Article : Google Scholar : PubMed/NCBI
12	Han R, Ji X, Rong R, Li Y, Yao W, Yuan J, Wu Q, Yang J, Yan W, Han L, et al: MiR-449a regulates autophagy to inhibit silica-induced pulmonary fibrosis through targeting Bcl2. J Mol Med (Berl). 94:1267–1279. 2016. View Article : Google Scholar : PubMed/NCBI
13	Renshaw A and Elsheikh TM: A validation study of the Focalpoint GS imaging system for gynecologic cytology screening. Cancer Cytopathol. 121:737–738. 2013. View Article : Google Scholar : PubMed/NCBI
14	Sun BS, Dong QZ, Ye QH, Sun HJ, Jia HL, Zhu XQ, Liu DY, Chen J, Xue Q, Zhou HJ, et al: Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology. 48:1834–1842. 2008. View Article : Google Scholar : PubMed/NCBI
15	Aguileta MA, Rojas-Rivera D, Goossens V, Estornes Y, Van Isterdael G, Vandenabeele P and Bertrand MJ: A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress. Cell Death Differ. 23:1670–1680. 2016. View Article : Google Scholar : PubMed/NCBI
16	Xiao S, Wang J and Xiao N: MicroRNAs as noninvasive biomarkers in bladder cancer detection: A diagnostic meta-analysis based on qRT-PCR data. Int J Biol Markers. 31:e276–e285. 2016. View Article : Google Scholar : 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 : PubMed/NCBI
18	Kotecha J, Atkins C and Wilson A: Patient confidence and quality of life in idiopathic pulmonary fibrosis and sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 33:341–348. 2016.PubMed/NCBI
19	Fu N, Niu X, Wang Y, Du H, Wang B, Du J, Li Y, Wang R, Zhang Y, Zhao S, et al: Role of LncRNA-activated by transforming growth factor beta in the progression of hepatitis C virus-related liver fibrosis. Discov Med. 22:29–42. 2016.PubMed/NCBI
20	Yin S, Zhang Q, Yang J, Lin W, Li Y, Chen F and Cao W: TGFbeta-incurred epigenetic aberrations of miRNA and DNA methyltransferase suppress Klotho and potentiate renal fibrosis. Biochim Biophys Acta. 2017. View Article : Google Scholar
21	Oglesby IK, Agrawal R, Mall MA, McElvaney NG and Greene CM: miRNA-221 is elevated in cystic fibrosis airway epithelial cells and regulates expression of ATF6. Mol Cell Pediatr. 2:12015. View Article : Google Scholar : PubMed/NCBI
22	Malik R, Patel L, Prensner JR, Shi Y, Iyer MK, Subramaniyan S, Carley A, Niknafs YS, Sahu A, Han S, et al: The lncRNA PCAT29 inhibits oncogenic phenotypes in prostate cancer. Mol Cancer Res. 12:1081–1087. 2014. View Article : Google Scholar : PubMed/NCBI
23	Lee CM, Park JW, Cho WK, Zhou Y, Han B, Yoon PO, Chae J, Elias JA and Lee CG: Modifiers of TGF-β1 effector function as novel therapeutic targets of pulmonary fibrosis. Korean J Int Med. 29:281–290. 2014. View Article : Google Scholar
24	Kang HR, Lee JY and Lee CG: TGF-beta1 as a therapeutic target for pulmonary fibrosis and COPD. Exp Rev Clin Pharmacol. 1:547–558. 2008. View Article : Google Scholar
25	Xu YD, Hua J, Mui A, O'Connor R, Grotendorst G and Khalil N: Release of biologically active TGF-beta1 by alveolar epithelial cells results in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 285:L527–L539. 2003. View Article : Google Scholar : PubMed/NCBI
26	Mao Y: Hypermethylation of RASAL1: A key for renal fibrosis. EBio Med. 2:7–8. 2015.
27	Tao H, Huang C, Yang JJ, Ma TT, Bian EB, Zhang L, Lv XW, Jin Y and Li J: MeCP2 controls the expression of RASAL1 in the hepatic fibrosis in rats. Toxicology. 290:327–333. 2011. View Article : Google Scholar : PubMed/NCBI
28	Hong Y, Han YQ, Wang YZ, Gao JR, Li YX, Liu Q and Xia LZ: Paridis Rhizoma Sapoinins attenuates liver fibrosis in rats by regulating the expression of RASAL1/ERK1/2 signal pathway. J Ethnopharmacol. 192:114–122. 2016. View Article : Google Scholar : PubMed/NCBI
29	Li S, Xu X, Geng J, Huang X, Jiang D, Zhu M and Dai H: Role and underlying mechanism of IGF-I/ERK signaling pathway in lung fibrosis. Zhonghua Yi Xue Za Zhi. 95:1615–1618. 2015.(In Chinese). PubMed/NCBI
30	Leask A: MEK/ERK inhibitors: Proof-of-concept studies in lung fibrosis. J Cell Commun Signal. 6:59–60. 2012. View Article : Google Scholar : PubMed/NCBI
31	Zuo WL, Zhao JM, Huang JX, Zhou W, Lei ZH, Huang YM, Huang YF and Li HG: Effect of bosentan is correlated with MMP-9/TIMP-1 ratio in bleomycin-induced pulmonary fibrosis. Biomed Rep. 6:201–205. 2017. View Article : Google Scholar : PubMed/NCBI