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miR-26a suppresses EMT by disrupting the Lin28B/let-7d axis: potential cross-talks among miRNAs in IPF

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and highly lethal fibrotic lung disease with unknown cause or cure. Although some microRNAs (miRNAs), such as miR-26a and let-7d, have been confirmed, the contribution to the pathophysiological processes of IPF, the roles of miRNAs and intrinsic links between them in fibrotic lung diseases are not yet well understood. In this study, we found that Lin28B could induce the process of epithelial-mesenchymal transition (EMT) by inhibiting let-7d, whereas inhibition of Lin28B mitigated TGF-β1-induced fibrogenesis and attenuated EMT in both cultured A549 cells and MLE-12 cells. More importantly, over-expression of miR-26a could simultaneously enhance the expression of let-7d in A549 cells, and further study confirmed that Lin28B was one of the direct targets of miR-26a, which mediates, at least in part, the regulatory effects of miR-26a on the biogenesis of let-7d. Finally, we constructed a regulatory network among miRNAs involved in the progression of IPF. Taken together, our study deciphered the essential role of Lin28B in the pathogenesis of EMT, and unraveled a novel mechanism that miR-26a is a modulator of let-7d. This study also defines the miRNAs network involved in IPF, which may have implications for developing new strategies for pulmonary fibrosis.

Key message

  • Upregulation of Lin28B contributes to idiopathic pulmonary fibrosis.

  • Lin28B causes epithelial-mesenchymal transition (EMT) by inhibition of let-7d.

  • Lin28B is one of the targets of microRNA-26a.

  • miR-26a enhances the expression of let-7d via targeting regulation of Lin28B.

  • A regulatory network among miRNAs involved in the progression of IPF.

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Acknowledgments

This study was supported by National Basic Research Program of China (973 program, 2013CB531104); the Funds for Creative Research Groups of the National Natural Science Foundation of China (grant 81421063); the National Natural Science Foundation of China (31300943, 31450009); the Research Fund for the Doctoral Program of Higher Education of China (20132307110004); the Scientific Fund of Heilongjiang Province for Youth (QC2015100), and the Heilongjiang Postdoctoral Foundation (LBH-TZ0617).

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    Authors and Affiliations

    1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Xuefu Road 194, Harbin, Heilongjiang, 150081, People’s Republic of China

      Haihai Liang, Shanshan Liu, Yang Chen, Xue Bai, Li Liu, Yuechao Dong, Meiyu Hu, Xiaomin Su, Longtao Huangfu, Xuelian Li & Hongli Shan

    2. Department of Pathology, the 2nd Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China

      Yingzhun Chen

    3. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China

      Yunyan Gu

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    1. Haihai Liang
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    Correspondence to Hongli Shan.

    Ethics declarations

    IPF lung tissue samples were obtained from surgical remnants of biopsies, and control samples were obtained from resected tissues from patients with lung cancer through the Second Affiliated Hospital of the Harbin Medical University under the procedures approved by the Ethics Committee for Use of Human Samples of Harbin Medical University (Harbin, China). Animals (8-week-old C57BL/6 mice; 20–30 g) used in this work were in accordance with the regulations of the Ethics Committees of Harbin Medical University and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996).

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    The authors declare that they have no competing interests.

    Additional information

    Haihai Liang, Shanshan Liu and Yang Chen contributed equally to this work.

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    Liang, H., Liu, S., Chen, Y. et al. miR-26a suppresses EMT by disrupting the Lin28B/let-7d axis: potential cross-talks among miRNAs in IPF. J Mol Med 94, 655–665 (2016). https://doi.org/10.1007/s00109-016-1381-8

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