Krüpple-like-factor 4 Attenuates Lung Fibrosis Via Inhibiting Epithelial-mesenchymal Transition

Overview

Journal Sci Rep

Specialty Science

Date 2017 Nov 22

PMID 29158503

Citations 31

Authors

Lianjun Lin

Qian Han

Yan Xiong

Ting Li

Zhonghui Liu

Huiying Xu

Yanping Wu

Nanping Wang

Xinmin Liu

Affiliations

Soon will be listed here.

Abstract

Epithelial-mesenchymal transition (EMT) plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Krüpple-like-factor 4 (KLF4), has been suggested to play an important role in the phenotype transition. However, its function in pulmonary fibrosis and EMT of human alveolar epithelial cells (AECs) remains unclear. This study aimed to examine the role of KLF4 in pulmonary fibrosis and EMT. Decreased expression of KLF4 was first observed in human IPF lung tissues and models of bleomycin-induced pulmonary fibrosis. Transgenic mice with overexpression of KLF4 were subjected to bleomycin-induced pulmonary fibrosis model and showed attenuated lung fibrosis and EMT compared to wild type group. Furthermore, the effects overexpression and knockdown of KLF4 on TGF-β1-induced EMT were examined in AECs. Adenovirus-mediated overexpression of KLF4 attenuated TGF-β1-induced EMT and activation of Smad2/3 and Dvl in AECs. Conversely, knockdown of KLF4 promoted the activation of pathways above mentioned and TGF-β1-induced EMT. Our results demonstrates that KLF4 plays an important role in bleomycin-induced lung fibrosis through suppressing TGFβ1-induced EMT. Thus, it may serve as a potential target for the treatment of pulmonary fibrosis.

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References

Shields J, Christy R, Yang V . Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest. J Biol Chem. 1996; 271(33):20009-17. PMC: 2330254. DOI: 10.1074/jbc.271.33.20009. View

Turner J, Crossley M . Mammalian Krüppel-like transcription factors: more than just a pretty finger. Trends Biochem Sci. 1999; 24(6):236-40. DOI: 10.1016/s0968-0004(99)01406-1. View

Wu Z, Yang L, Cai L, Zhang M, Cheng X, Yang X . Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an alpha-smooth muscle actin-Cre transgenic mouse. Respir Res. 2007; 8:1. PMC: 1781437. DOI: 10.1186/1465-9921-8-1. View

Jean J, George E, Kaestner K, Brown L, Spira A, Joyce-Brady M . Transcription factor Klf4, induced in the lung by oxygen at birth, regulates perinatal fibroblast and myofibroblast differentiation. PLoS One. 2013; 8(1):e54806. PMC: 3553006. DOI: 10.1371/journal.pone.0054806. View

Phan S . The myofibroblast in pulmonary fibrosis. Chest. 2002; 122(6 Suppl):286S-289S. DOI: 10.1378/chest.122.6_suppl.286s. View

Lin Z, Chu H, Yen Y, Lewis B, Chen Y . Krüppel-like factor 4, a tumor suppressor in hepatocellular carcinoma cells reverts epithelial mesenchymal transition by suppressing slug expression. PLoS One. 2012; 7(8):e43593. PMC: 3427336. DOI: 10.1371/journal.pone.0043593. View

Selman M, King T, Pardo A . Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001; 134(2):136-51. DOI: 10.7326/0003-4819-134-2-200101160-00015. View

Cowan C, Kohler E, Dugan T, Mirza M, Malik A, Wary K . Kruppel-like factor-4 transcriptionally regulates VE-cadherin expression and endothelial barrier function. Circ Res. 2010; 107(8):959-66. PMC: 3018700. DOI: 10.1161/CIRCRESAHA.110.219592. View

Narla G, DiFeo A, Reeves H, Schaid D, Hirshfeld J, Hod E . A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res. 2005; 65(4):1213-22. DOI: 10.1158/0008-5472.CAN-04-4249. View

10.

Willis B, duBois R, Borok Z . Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc. 2006; 3(4):377-82. PMC: 2658689. DOI: 10.1513/pats.200601-004TK. View

11.

Massague J . How cells read TGF-beta signals. Nat Rev Mol Cell Biol. 2001; 1(3):169-78. DOI: 10.1038/35043051. View

12.

Selman M, Pardo A . Idiopathic pulmonary fibrosis: misunderstandings between epithelial cells and fibroblasts?. Sarcoidosis Vasc Diffuse Lung Dis. 2004; 21(3):165-72. View

13.

Sun F, Hu K . Krüppel-Like Factor 4 Inhibits the Transforming Growth Factor-β1-Promoted Epithelial-to-Mesenchymal Transition via Downregulating Plasminogen Activator Inhibitor-1 in Lung Epithelial Cells. Dis Markers. 2016; 2015:473742. PMC: 4709646. DOI: 10.1155/2015/473742. View

14.

Wang Y, Zhao B, Zhang Y, Tang Z, Shen Q, Zhang Y . Krüppel-like factor 4 is induced by rapamycin and mediates the anti-proliferative effect of rapamycin in rat carotid arteries after balloon injury. Br J Pharmacol. 2011; 165(7):2378-88. PMC: 3413870. DOI: 10.1111/j.1476-5381.2011.01734.x. View

15.

Suske G, Bruford E, Philipsen S . Mammalian SP/KLF transcription factors: bring in the family. Genomics. 2005; 85(5):551-6. DOI: 10.1016/j.ygeno.2005.01.005. View

16.

Kim K, Kugler M, Wolters P, Robillard L, Galvez M, Brumwell A . Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006; 103(35):13180-5. PMC: 1551904. DOI: 10.1073/pnas.0605669103. View

17.

Willis B, Liebler J, Luby-Phelps K, Nicholson A, Crandall E, du Bois R . Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol. 2005; 166(5):1321-32. PMC: 1606388. DOI: 10.1016/s0002-9440(10)62351-6. View

18.

Hu W, Hofstetter W, Li H, Zhou Y, He Y, Pataer A . Putative tumor-suppressive function of Kruppel-like factor 4 in primary lung carcinoma. Clin Cancer Res. 2009; 15(18):5688-95. PMC: 2745510. DOI: 10.1158/1078-0432.CCR-09-0310. View

19.

Schurch W, Seemayer T, Gabbiani G . The myofibroblast: a quarter century after its discovery. Am J Surg Pathol. 1998; 22(2):141-7. DOI: 10.1097/00000478-199802000-00001. View

20.

Xiao X, Tang W, Yuan Q, Peng L, Yu P . Epigenetic repression of Krüppel-like factor 4 through Dnmt1 contributes to EMT in renal fibrosis. Int J Mol Med. 2015; 35(6):1596-602. PMC: 4432929. DOI: 10.3892/ijmm.2015.2189. View