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Cited by 104Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisMicroRNA in disease regulationTelomeres, Telomerase, and Senescence

miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence

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Cui, Huachun, Ge, Jing, Xie, Na, Banerjee, Sami, Zhou, Yong, Antony, Veena B., Thannickal, Victor J., Liu, Gang·2017·American Journal of Respiratory Cell and Molecular Biology
DOI 10.1165/rcmb.2016-0163ocPMC PMC5359651
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Abstract

Cellular senescence has been implicated in diverse pathologies. However, there is conflicting evidence regarding the role of this process in tissue fibrosis. Although dysregulation of microRNAs is a key mechanism in the pathogenesis of lung fibrosis, it is unclear whether microRNAs function by regulating cellular senescence in the disease. In this study, we found that miR-34a demonstrated greater expression in the lungs of patients with idiopathic pulmonary fibrosis and in mice with experimental pulmonary fibrosis, with its primary localization in lung fibroblasts. More importantly, miR-34a was up-regulated significantly in both human and mouse lung myofibroblasts. We found that mice with miR-34a ablation developed more severe pulmonary fibrosis than did wild-type animals after fibrotic lung injury. Mechanistically, we found that miR-34a induced a senescent phenotype in lung fibroblasts because this microRNA increased senescence-associated β-galactosidase activity, enhanced expression of senescence markers, and decreased cell proliferative capacities. Consistently, we found that primary lung fibroblasts from fibrotic lungs of miR-34a–deficient mice had a diminished senescent phenotype and enhanced resistance to apoptosis as compared with those from wild-type animals. We also identified multiple miR-34a targets that likely mediated its activities in inducing senescence in lung fibroblasts. In conclusion, our data suggest that miR-34a functions through a negative feedback mechanism to restrain fibrotic response in the lungs by promoting senescence of pulmonary fibroblasts.

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  1. [1]Noble PW, Barkauskas CE, Jiang D. Pulmonary fibrosis: patterns and perpetrators. J Clin Invest. 2012;122:2756–2762. doi: 10.1172/JCI60323. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  2. [2]Thannickal VJ, Zhou Y, Gaggar A, Duncan SR. Fibrosis: ultimate and proximate causes. J Clin Invest. 2014;124:4673–4677. doi: 10.1172/JCI74368. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  3. [3]Barkauskas CE, Noble PW. Cellular mechanisms of tissue fibrosis. 7. New insights into the cellular mechanisms of pulmonary fibrosis. Am J Physiol Cell Physiol. 2014;306:C987–C996. doi: 10.1152/ajpcell.00321.2013. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  4. [4]Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014;9:157–179. doi: 10.1146/annurev-pathol-012513-104706. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  5. [7]Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621. doi: 10.1016/0014-4827(61)90192-6. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  6. [8]van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509:439–446. doi: 10.1038/nature13193. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  7. [10]Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol. 2010;12:676–685. doi: 10.1038/ncb2070. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  8. [11]Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, Meldrum E, Sanders YY, Thannickal VJ. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med. 2014;6:231ra47. doi: 10.1126/scitranslmed.3008182. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  9. [12]Zhu F, Li Y, Zhang J, Piao C, Liu T, Li HH, Du J. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS One. 2013;8:e74535. doi: 10.1371/journal.pone.0074535. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  10. [13]Shivshankar P, Brampton C, Miyasato S, Kasper M, Thannickal VJ, Le Saux CJ. Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice. Am J Respir Cell Mol Biol. 2012;47:28–36. doi: 10.1165/rcmb.2011-0349OC. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  11. [15]Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012;148:1172–1187. doi: 10.1016/j.cell.2012.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  12. [16]Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, Kaminski N, Abraham E. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med. 2010;207:1589–1597. doi: 10.1084/jem.20100035. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  13. [17]Yang S, Cui H, Xie N, Icyuz M, Banerjee S, Antony VB, Abraham E, Thannickal VJ, Liu G. miR-145 regulates myofibroblast differentiation and lung fibrosis. FASEB J. 2013;27:2382–2391. doi: 10.1096/fj.12-219493. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  14. [18]Pagdin T, Lavender P. MicroRNAs in lung diseases. Thorax. 2012;67:183–184. doi: 10.1136/thoraxjnl-2011-200532. [DOI] [PubMed] [Google Scholar] · DOI
  15. [19]Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, Thannickal VJ, Cardoso WV, Lü J. miR-29 is a major regulator of genes associated with pulmonary fibrosis. Am J Respir Cell Mol Biol. 2011;45:287–294. doi: 10.1165/rcmb.2010-0323OC. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  16. [20]Yang S, Banerjee S, de Freitas A, Sanders YY, Ding Q, Matalon S, Thannickal VJ, Abraham E, Liu G. Participation of miR-200 in pulmonary fibrosis. Am J Pathol. 2012;180:484–493. doi: 10.1016/j.ajpath.2011.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  17. [21]Pandit KV, Milosevic J. MicroRNA regulatory networks in idiopathic pulmonary fibrosis. Biochem Cell Biol. 2015;93:129–137. doi: 10.1139/bcb-2014-0101. [DOI] [PubMed] [Google Scholar] · DOI
  18. [22]Su S, Zhao Q, He C, Huang D, Liu J, Chen F, Chen J, Liao JY, Cui X, Zeng Y, et al. miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program. Nat Commun. 2015;6:8523. doi: 10.1038/ncomms9523. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  19. [23]Cui H, Xie N, Tan Z, Liu RM, Ding Q, Zhou Y, Andrade JA, Luckhardt TR, Antony VB, Thannickal VJ, et al. miR-34a regulates senescence of lung fibroblasts and lung fibrosis [abstract] Am J Respir Crit Care Med. 2015;191:A5317. [Google Scholar]
  20. [25]Cui H, Banerjee S, Xie N, Ge J, Liu RM, Matalon S, Thannickal VJ, Liu G. MicroRNA-27a-3p is a negative regulator of lung fibrosis by targeting myofibroblast differentiation. Am J Respir Cell Mol Biol. 2016;54:843–852. doi: 10.1165/rcmb.2015-0205OC. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  21. [26]Liu G, Park YJ, Abraham E. Interleukin-1 receptor-associated kinase (IRAK)-1-mediated NF-κB activation requires cytosolic and nuclear activity. FASEB J. 2008;22:2285–2296. doi: 10.1096/fj.07-101816. [DOI] [PubMed] [Google Scholar] · DOI
  22. [27]Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci USA. 2007;104:15472–15477. doi: 10.1073/pnas.0707351104. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  23. [28]Kumamoto K, Spillare EA, Fujita K, Horikawa I, Yamashita T, Appella E, Nagashima M, Takenoshita S, Yokota J, Harris CC. Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. Cancer Res. 2008;68:3193–3203. doi: 10.1158/0008-5472.CAN-07-2780. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  24. [29]Christoffersen NR, Shalgi R, Frankel LB, Leucci E, Lees M, Klausen M, Pilpel Y, Nielsen FC, Oren M, Lund AH. p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ. 2010;17:236–245. doi: 10.1038/cdd.2009.109. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  25. [31]Fernandez IE, Eickelberg O. The impact of TGF-β on lung fibrosis: from targeting to biomarkers. Proc Am Thorac Soc. 2012;9:111–116. doi: 10.1513/pats.201203-023AW. [DOI] [PubMed] [Google Scholar] · DOI
  26. [32]Li Y, Liang J, Yang T, Monterrosa Mena J, Huan C, Xie T, Kurkciyan A, Liu N, Jiang D, Noble PW. Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis. Matrix Biol. 2016;55:35–48. doi: 10.1016/j.matbio.2016.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  27. [34]Zhou Y, Huang X, Hecker L, Kurundkar D, Kurundkar A, Liu H, Jin TH, Desai L, Bernard K, Thannickal VJ. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest. 2013;123:1096–1108. doi: 10.1172/JCI66700. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  28. [36]Bhatia-Dey N, Kanherkar RR, Stair SE, Makarev EO, Csoka AB. Cellular senescence as the causal nexus of aging. Front Genet. 2016;7:13. doi: 10.3389/fgene.2016.00013. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  29. [37]Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–740. doi: 10.1038/nrm2233. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  30. [38]Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007;130:223–233. doi: 10.1016/j.cell.2007.07.003. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  31. [39]Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15:482–496. doi: 10.1038/nrm3823. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  32. [40]Pitiyage GN, Slijepcevic P, Gabrani A, Chianea YG, Lim KP, Prime SS, Tilakaratne WM, Fortune F, Parkinson EK. Senescent mesenchymal cells accumulate in human fibrosis by a telomere-independent mechanism and ameliorate fibrosis through matrix metalloproteinases. J Pathol. 2011;223:604–617. doi: 10.1002/path.2839. [DOI] [PubMed] [Google Scholar] · DOI
  33. [41]Cui H, Xie N, Thannickal VJ, Liu G. The code of non-coding RNAs in lung fibrosis. Cell Mol Life Sci. 2015;72:3507–3519. doi: 10.1007/s00018-015-1939-6. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  34. [42]Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013;123:966–972. doi: 10.1172/JCI64098. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  35. [44]He C, Ryan AJ, Murthy S, Carter AB. Accelerated development of pulmonary fibrosis via Cu,Zn-superoxide dismutase-induced alternative activation of macrophages. J Biol Chem. 2013;288:20745–20757. doi: 10.1074/jbc.M112.410720. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  36. [45]Larson-Casey JL, Deshane JS, Ryan AJ, Thannickal VJ, Carter AB. Macrophage Akt1 kinase-mediated mitophagy modulates apoptosis resistance and pulmonary fibrosis. Immunity. 2016;44:582–596. doi: 10.1016/j.immuni.2016.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page

Cited by

Sorted by citations

Authors
Cui, H., Ge, J., Xie, N., Banerjee, S., Zhou, Y., Antony, V. B., Thannickal, V. J., & Liu, G.
Affiliations
University of Alabama at Birmingham (US)
Corresponding author
Liu, Gang
ORCID
Venue
American Journal of Respiratory Cell and Molecular Biology
Publisher
Oxford University Press (OUP)
Published
2017-02-01
Volume
56
Issue
2
Pages
168-178
ISSN
  • 1044-1549 (ISSN-L)
  • 1535-4989
DOI
10.1165/rcmb.2016-0163oc
PMC
PMC5359651
OpenAlex
W2520496393
Cited by
104
References
10
Citations by year
2026: 6 · 2025: 5 · 2024: 4 · 2023: 15 · 2022: 8 · 2021: 8 · 2020: 21 · 2019: 16 · 2018: 10 · 2017: 9 · 2016: 2
FWCI
11.03
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL126737, R01HL124076, R01HL105473, R35HL135830, P01HL114470)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
miR-34a, pulmonary fibrosis, idiopathic pulmonary fibrosis, cellular senescence, lung fibroblasts, myofibroblasts, microRNA, senescence-associated β-galactosidase, apoptosis resistance, miRNA target genes, negative feedback regulation
MeSH terms
Animals, Cell Differentiation, Fibroblasts, Humans, Lung, Mice, Inbred C57BL, Up-Regulation, Cellular Senescence, Apoptosis, MicroRNAs, Transforming Growth Factor beta1, Idiopathic Pulmonary Fibrosis, Gene Knockdown Techniques, Myofibroblasts

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