Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by lung fibroblasts accumulation and extracellular matrix (ECM) deposition. Recently, long-noncoding RNAs (lncRNAs) have emerged as critical regulators and prognostic markers in several diseases including IPF. In the present study, we found that the expression of H19 was significantly increased in transforming growth factor-β (TGF-β)-induced fibroblast proliferation and bleomycin-(BLM) induced lung fibrosis (p < 0.05). We further demonstrated that H19 was a direct target of miR-196a and was associated with COL1A1 expression by sponging miR-196a. Moreover, downregulation of H19 alleviated fibroblast activation and lung fibrosis, and this effect was blocked by a miR-196a inhibitor. In conclusion, our results suggest that lncRNA H19 has a promotive effect on BLM-induced IPF, and it functions as a molecular sponge of miR-196a, which provides a novel therapeutic target for IPF.
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References
King, T.E., Jr., A. Pardo, and M. Selman. 2011. Idiopathic pulmonary fibrosis. Lancet 378 (9807): 1949–1961.
Lee, Y.J., M.J. Kim, Y.S. Yoon, Y.H. Choi, H.S. Kim, and J.L. Kang. 2017. Simvastatin treatment boosts benefits of apoptotic cell infusion in murine lung fibrosis. Cell Death & Disease 8 (6): e2860.
Wu, D.D., X. Chen, K.X. Sun, L.L. Wang, S. Chen, and Y. Zhao. 2017. Role of the lncRNA ABHD11-AS1 in the tumorigenesis and progression of epithelial ovarian cancer through targeted regulation of RhoC. Molecular Cancer 16 (1): 138.
Xie, H., J.D. Xue, F. Chao, Y.F. Jin, and Q. Fu. 2016. Long non-coding RNA-H19 antagonism protects against renal fibrosis. Oncotarget 7 (32): 51473–51481.
Qu, X., X. Song, W. Yuan, Y. Shu, Y. Wang, X. Zhao, M. Gao, R. Lu, S. Luo, W. Zhao, Y. Zhang, L. Sun, and Y. Lu. 2016. Expression signature of lncRNAs and their potential roles in cardiac fibrosis of post-infarct mice. Bioscience Reports 36 (3): e00337.
Huang, C., Y. Yang, and L. Liu. 2015. Interaction of long noncoding RNAs and microRNAs in the pathogenesis of idiopathic pulmonary fibrosis. Physiological Genomics 47 (10): 463–469.
Raveh, E., I.J. Matouk, M. Gilon, and A. Hochberg. 2015. The H19 long non-coding RNA in cancer initiation, progression and metastasis - a proposed unifying theory. Molecular Cancer 14: 184.
Tang, Y., R. He, J. An, P. Deng, L. Huang, and W. Yang. 2016. The effect of H19-miR-29b interaction on bleomycin-induced mouse model of idiopathic pulmonary fibrosis. Biochemical and Biophysical Research Communications 479 (3): 417–423.
Tong, H.L., R.Y. Jiang, W.W. Zhang, and Y.Q. Yan. 2017. MiR-2425-5p targets RAD9A and MYOG to regulate the proliferation and differentiation of bovine skeletal muscle-derived satellite cells. Scientific Reports 7 (1): 418.
Mizuno, K., H. Mataki, N. Seki, T. Kumamoto, K. Kamikawaji, and H. Inoue. 2017. MicroRNAs in non-small cell lung cancer and idiopathic pulmonary fibrosis. Journal of Human Genetics 62 (1): 57–65.
Ji, X., B. Wu, J. Fan, R. Han, C. Luo, T. Wang, J. Yang, L. Han, B. Zhu, D. Wei, J. Chen, and C. Ni. 2015. The anti-fibrotic effects and mechanisms of microRNA-486-5p in pulmonary fibrosis. Scientific Reports 5: 14131.
Wu, Q., L. Han, W. Yan, X. Ji, R. Han, J. Yang, J. Yuan, and C. Ni. 2016. miR-489 inhibits silica-induced pulmonary fibrosis by targeting MyD88 and Smad3 and is negatively regulated by lncRNA CHRF. Scientific Reports 6 (30921).
Jin, C., Y. Zhang, and J. Li. 2016. Upregulation of MiR-196a promotes cell proliferation by downregulating p27kip1 in laryngeal cancer. Biological Research 49 (1): 40.
Ma, Y., B. Wang, Y. Guo, Y. Zhang, S. Huang, X. Bao, and M. Bai. 2016. Inhibition of miR-196a affects esophageal cancer cell growth in vitro. Biomedicine & Pharmacotherapy 84: 22–27.
Meng, J., L. Li, Y. Zhao, Z. Zhou, M. Zhang, D. Li, C.Y. Zhang, K. Zen, and Z. Liu. 2016. MicroRNA-196a/b mitigate renal fibrosis by targeting TGF-beta receptor 2. Journal of the American Society of Nephrology 27 (10): 3006–3021.
Kashiyama, K., N. Mitsutake, M. Matsuse, T. Ogi, V.A. Saenko, K. Ujifuku, A. Utani, A. Hirano, and S. Yamashita. 2012. miR-196a downregulation increases the expression of type I and III collagens in keloid fibroblasts. The Journal of Investigative Dermatology 132 (6): 1597–1604.
Delas, M.J., and G.J. Hannon. 2017. lncRNAs in development and disease: from functions to mechanisms. Open Biology 7 (7): 170121.
Kung, J.T., D. Colognori, and J.T. Lee. 2013. Long noncoding RNAs: past, present, and future. Genetics 193 (3): 651–669.
Wang, K.C., and H.Y. Chang. 2011. Molecular mechanisms of long noncoding RNAs. Molecular Cell 43 (6): 904–914.
Schmitt, A.M., and H.Y. Chang. 2016. Long noncoding RNAs in cancer pathways. Cancer Cell 29 (4): 452–463.
Wang, S.H., F. Ma, Z.H. Tang, X.C. Wu, Q. Cai, M.D. Zhang, M.Z. Weng, D. Zhou, J.D. Wang, and Z.W. Quan. 2016. Long non-coding RNA H19 regulates FOXM1 expression by competitively binding endogenous miR-342-3p in gallbladder cancer. Journal of Experimental & Clinical Cancer Research 35 (1): 160.
Su, Z., X. Zhi, Q. Zhang, L. Yang, H. Xu, and Z. Xu. 2016. LncRNA H19 functions as a competing endogenous RNA to regulate AQP3 expression by sponging miR-874 in the intestinal barrier. FEBS Letters 590 (9): 1354–1364.
Shen, L., G. Zhang, Z. Lou, and G. Xu. 2017. Cryptotanshinone enhances the effect of arsenic trioxide in treating liver cancer cell by inducing apoptosis through downregulating phosphorylated- STAT3 in vitro and in vivo. BMC Complementary and Alternative Medicine 17 (1): 106.
Sun, H., J. Chen, W. Qian, J. Kang, J. Wang, L. Jiang, L. Qiao, W. Chen, and J. Zhang. 2016. Integrated long non-coding RNA analyses identify novel regulators of epithelial-mesenchymal transition in the mouse model of pulmonary fibrosis. Journal of Cellular and Molecular Medicine 20 (7): 1234–1246.
Salmena, L., L. Poliseno, Y. Tay, L. Kats, and P.P. Pandolfi. 2011. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146 (3): 353–358.
Dong, J., and Q. Ma. 2016. Myofibroblasts and lung fibrosis induced by carbon nanotube exposure. Particle and Fibre Toxicology 13 (1): 60.
Burgess, J.K., T. Mauad, G. Tjin, J.C. Karlsson, and G. Westergren-Thorsson. 2016. The extracellular matrix—the under-recognized element in lung disease? The Journal of Pathology 240 (4): 397–409.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China [grant numbers 81673014, 81372347, and 81370174], Outstanding Academic Leaders Plan of Shanghai Municipal Science and Technology Committee [grant number 16XD1403100], and National Key R&D Plan [grant number 2017YFA0104600].
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Qingchun Lu and Zhongliang Guo contributed equally to this work.
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Lu, Q., Guo, Z., Xie, W. et al. The lncRNA H19 Mediates Pulmonary Fibrosis by Regulating the miR-196a/COL1A1 Axis. Inflammation 41, 896–903 (2018). https://doi.org/10.1007/s10753-018-0744-4
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DOI: https://doi.org/10.1007/s10753-018-0744-4