Knockdown of FSTL1 inhibits PDGF‑BB‑induced human airway smooth muscle cell proliferation and migration

Deng,Yuelin; Zhang,Yao; Wu,Huajie; Shi,Zhaoling; Sun,Xin

doi:10.3892/mmr.2017.6439

Knockdown of FSTL1 inhibits PDGF‑BB‑induced human airway smooth muscle cell proliferation and migration

Authors:
- Yuelin Deng
- Yao Zhang
- Huajie Wu
- Zhaoling Shi
- Xin Sun
View Affiliations

Affiliations: Department of Pediatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: April 7, 2017 https://doi.org/10.3892/mmr.2017.6439
Pages: 3859-3864

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

Abnormal proliferation and migration of airway smooth muscle (ASM) cells serve roles in airway remodeling, and contribute to airway hyper‑responsiveness. Follistatin‑like protein 1 (FSTL1) is a secreted glycoprotein that belongs to the follistatin family of proteins. It was reported that in the lungs of patients suffering from severe asthma, FSTL1 is highly expressed by macrophages. However, the role of FSTL1 in ASM cell proliferation and migration remains unknown. The present study aimed to investigate the role of FSTL1 in cell proliferation and migration mediated by platelet‑derived growth factor subunit B (PDGF‑BB) in human ASM cells. The results of the present study demonstrated that PDGF‑BB stimulation upregulated FSTL1 expression levels in ASM cells in vitro. Knockdown of FSTL1 inhibited cell proliferation and arrested the cell cycle in the G2/M phase in PDGF‑BB‑stimulated ASM cells. Additionally, knockdown of FSTL1 inhibited PDGF‑BB‑induced ASM cell migration. Furthermore, FSTL1 knockdown caused the downregulation of phosphorylated (p)‑extracellular signal‑regulated kinase (ERK) and p‑protein kinase B (AKT) expression levels induced by PDGF‑BB in ASM cells. In conclusion, the present study demonstrated that knockdown of FSTL1 inhibited ASM cell proliferation and migration induced by PDGF‑BB, at least partially via inhibiting the activation of ERK and AKT. FSTL1 may therefore represent a novel therapeutic target for airway remodeling in childhood asthma.

View Figures

View References

1	Noutsios GT and Floros J: Childhood asthma: Causes, risks, and protective factors; a role of innate immunity. Swiss Med Wkly. 144:w140362014.PubMed/NCBI
2	Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK and Williams H; ISAAC Phase Three Study Group, : Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 368:733–743. 2006. View Article : Google Scholar : PubMed/NCBI
3	De Marco R, Cappa V, Accordini S, Rava M, Antonicelli L, Bortolami O, Braggion M, Bugiani M, Casali L, Cazzoletti L, et al: Trends in the prevalence of asthma and allergic rhinitis in Italy between 1991 and 2010. Eur Respir J. 39:883–892. 2012. View Article : Google Scholar : PubMed/NCBI
4	Zuyderduyn S, Sukkar M, Fust A, Dhaliwal S and Burgess JK: Treating asthma means treating airway smooth muscle cells. Eur Respir J. 32:265–274. 2008. View Article : Google Scholar : PubMed/NCBI
5	Hirst SJ, Martin JG, Bonacci JV, Chan V, Fixman ED, Hamid QA, Herszberg B, Lavoie JP, McVicker CG, Moir LM, et al: Proliferative aspects of airway smooth muscle. J Allergy Clin Immunol. 114(2 Suppl): S2–S17. 2004. View Article : Google Scholar : PubMed/NCBI
6	Carlin SM, Roth M and Black JL: Urokinase potentiates PDGF-induced chemotaxis of human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 284:L1020–L1026. 2003. View Article : Google Scholar : PubMed/NCBI
7	Madison JM: Migration of airway smooth muscle cells. Am J Respir Cell Mol Biol. 29:8–11. 2003. View Article : Google Scholar : PubMed/NCBI
8	Parameswaran K, Radford K, Zuo J, Janssen L, O'byrne P and Cox P: Extracellular matrix regulates human airway smooth muscle cell migration. Eur Respir J. 24:545–551. 2004. View Article : Google Scholar : PubMed/NCBI
9	Le Luduec JB, Condamine T, Louvet C, Thebault P, Heslan JM, Heslan M, Chiffoleau E and Cuturi MC: An immunomodulatory role for follistatin-like 1 in heart allograft transplantation. Am J Transplant. 8:2297–2306. 2008. View Article : Google Scholar : PubMed/NCBI
10	Esterberg R, Delalande JM and Fritz A: Tailbud-derived Bmp4 drives proliferation and inhibits maturation of zebrafish chordamesoderm. Development. 135:3891–3901. 2008. View Article : Google Scholar : PubMed/NCBI
11	Ouchi N, Oshima Y, Ohashi K, Higuchi A, Ikegami C, Izumiya Y and Walsh K: Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J Biol Chem. 283:32802–32811. 2008. View Article : Google Scholar : PubMed/NCBI
12	Chan QK, Ngan HY, Ip PP, Liu VW, Xue WC and Cheung AN: Tumor suppressor effect of follistatin-like 1 in ovarian and endometrial carcinogenesis: A differential expression and functional analysis. Carcinogenesis. 30:114–121. 2009. View Article : Google Scholar : PubMed/NCBI
13	Miller M, Beppu A, Rosenthal P, Pham A, Das S, Karta M, Song DJ, Vuong C, Doherty T, Croft M, et al: Fstl1 promotes asthmatic airway remodeling by inducing oncostatin M. J Immunol. 195:3546–3556. 2015. View Article : Google Scholar : PubMed/NCBI
14	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
15	Geng Y, Dong Y, Yu M, Zhang L, Yan X, Sun J, Qiao L, Geng H, Nakajima M, Furuichi T, et al: Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development. Proc Natl Acad Sci USA. 108:pp. 7058–7063. 2011; View Article : Google Scholar : PubMed/NCBI
16	Dong Y, Geng Y, Li L, Li X, Yan X, Fang Y, Li X, Dong S, Liu X, Li X, et al: Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice. J Exp Med. 212:235–252. 2015. View Article : Google Scholar : PubMed/NCBI
17	Johnston I, Spence HJ, Winnie JN, McGarry L, Vass JK, Meagher L, Stapleton G and Ozanne BW: Regulation of a multigenic invasion programme by the transcription factor, AP-1: Re-expression of a down-regulated gene, TSC-36, inhibits invasion. Oncogene. 19:5348–5358. 2000. View Article : Google Scholar : PubMed/NCBI
18	Sumitomo K, Kurisaki A, Yamakawa N, Tsuchida K, Shimizu E, Sone S and Sugino H: Expression of a TGF-beta1 inducible gene, TSC-36, causes growth inhibition in human lung cancer cell lines. Cancer Lett. 155:37–46. 2000. View Article : Google Scholar : PubMed/NCBI
19	Wei Y, Xu YD, Yin LM, Wang Y, Ran J, Liu Q, Ma ZF, Liu YY and Yang YQ: Recombinant rat CC10 protein inhibits PDGF-induced airway smooth muscle cells proliferation and migration. Biomed Res Int. 2013:6909372013. View Article : Google Scholar : PubMed/NCBI
20	Liu W, Kong H, Zeng X, Wang J, Wang Z, Yan X, Wang Y, Xie W and Wang H: Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration. Exp Cell Res. 336:204–210. 2015. View Article : Google Scholar : PubMed/NCBI
21	Ning Y, Huang H, Dong Y, Sun Q, Zhang W, Xu W and Li Q: 5-Aza-2-deoxycytidine inhibited PDGF-induced rat airway smooth muscle cell phenotypic switching. Arch Toxicol. 87:871–881. 2013. View Article : Google Scholar : PubMed/NCBI
22	Day RM, Lee YH, Park AM and Suzuki YJ: Retinoic acid inhibits airway smooth muscle cell migration. Am J Respir Cell Mol Biol. 34:695–703. 2006. View Article : Google Scholar : PubMed/NCBI
23	Lee JH, Johnson PR, Roth M, Hunt NH and Black JL: ERK activation and mitogenesis in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 280:L1019–L1029. 2001.PubMed/NCBI
24	Xie S, Sukkar MB, Issa R, Oltmanns U, Nicholson AG and Chung KF: Regulation of TGF-beta 1-induced connective tissue growth factor expression in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 288:L68–L76. 2005. View Article : Google Scholar : PubMed/NCBI
25	Burgess JK, Lee JH, Ge Q, Ramsay EE, Poniris MH, Parmentier J, Roth M, Johnson PR, Hunt NH, Black JL and Ammit AJ: Dual ERK and phosphatidylinositol 3-kinase pathways control airway smooth muscle proliferation: Differences in asthma. J Cell Physiol. 216:673–679. 2008. View Article : Google Scholar : PubMed/NCBI
26	Stewart AG, Xia YC, Harris T, Royce S, Hamilton JA and Schuliga M: Plasminogen-stimulated airway smooth muscle cell proliferation is mediated by urokinase and annexin A2, involving plasmin-activated cell signalling. Br J Pharmacol. 170:1421–1435. 2013. View Article : Google Scholar : PubMed/NCBI
27	Oshima Y, Ouchi N, Sato K, Izumiya Y, Pimentel DR and Walsh K: Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart. Circulation. 117:3099–3108. 2008. View Article : Google Scholar : PubMed/NCBI
28	Movassagh H, Shan L, Halayko AJ, Roth M, Tamm M, Chakir J and Gounni AS: Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration. J Allergy Clin Immunol. 133:560–567. 2014. View Article : Google Scholar : PubMed/NCBI
29	Walker TR, Moore SM, Lawson MF, Panettieri RA Jr and Chilvers ER: Platelet-derived growth factor-BB and thrombin activate phosphoinositide 3-kinase and protein kinase B: Role in mediating airway smooth muscle proliferation. Mol Pharmacol. 54:1007–1015. 1998.PubMed/NCBI