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NEAT1 accelerates the progression of liver fibrosis via regulation of microRNA-122 and Kruppel-like factor 6

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Abstract

Long non-coding RNAs (lncRNAs) have been reported to be involved in many important biological processes including proliferation, apoptosis, differentiation, and survival. Recently, nuclear paraspeckle assembly transcript 1 (NEAT1), a novel lncRNA, serves as a crucial regulator in tumors. However, the biological role of NEAT1 in liver fibrosis is largely unknown. In this study, the role of NEAT1 was explored in primary mouse hepatic stellate cells (HSCs) and carbon tetrachloride (CCl4)-induced mouse liver fibrosis models. We found that NEAT1 expression was significantly increased in CCl4-induced mice and activated HSCs. Loss of NEAT1 suppressed liver fibrosis in vivo and in vitro. Conversely, NEAT1 overexpression accelerated HSC activation, including increased cell proliferation and collagen expression. Further studies indicated that the microRNA-122 (miR-122)-Kruppel-like factor 6 (KLF6) axis was involved in the effects of NEAT1 on HSC activation. The effects of NEAT1 on HSC activation were almost blocked down by miR-122 mimics or KLF6 knockdown. Interestingly, both NEAT1 and KLF6 are targets of miR-122. In addition, miR-122 led to a significant reduction in NEAT1 level while NEAT1 overexpression resulted in the suppression of miR-122 expression. Pull-down assay confirmed a direct interaction between miR-122 and NEAT1. NEAT1 contributes to HSC activation via the miR-122-KLF6 axis. In human fibrotic liver samples, increased NEAT1 levels positively correlated with liver fibrosis markers. In conclusion, we disclose a novel NEAT1-miR-122-KLF6 signaling cascade and its implication in liver fibrosis.

Key messages

  • NEAT1 was significantly increased in CCl4-induced mice and activated HSCs.

  • Loss of NEAT1 suppressed liver fibrosis in vivo and in vitro.

  • KLF6 and miR-122 were required for the effects of NEAT1 on HSC activation.

  • NEAT1 contributes to HSC activation via competitively binding miR-122.

  • We disclose a novel NEAT1-miR-122-KLF6 signaling cascade.

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Acknowledgements

The project was supported by the Zhejiang Provincial Natural Science Foundation of China (No. LY16H030012 and No. LY13H030006), National Natural Science Foundation of China (No. 81500458/H0317), and Wenzhou Municipal Science and technology Bureau (No. Y20150091).

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Author notes

  1. Fujun Yu and Zhe Jiang contributed equally.

Authors and Affiliations

  1. Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Fujun Yu & Peihong Dong

  2. Department of Blood Donation Service, Huadu Blood Station of Guangzhou Blood Center, Guangzhou, 510800, China

    Zhe Jiang

  3. Key Laboratory of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, No.2 fuxue lane, Wenzhou, 325000, Zhejiang, People’s Republic of China

    Bicheng Chen & Jianjian Zheng

  4. Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, No.2 fuxue lane, Wenzhou, Zhejiang, People’s Republic of China

    Peihong Dong

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  1. Fujun Yu
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  2. Zhe Jiang
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  3. Bicheng Chen
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  4. Peihong Dong
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Correspondence to Peihong Dong or Jianjian Zheng.

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All animals were provided by the Experimental Animal Center of Wenzhou Medical University. The animal experimental protocol was approved by the University Animal Care and Use Committee.

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The authors declare that they have no conflict of interest.

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Yu, F., Jiang, Z., Chen, B. et al. NEAT1 accelerates the progression of liver fibrosis via regulation of microRNA-122 and Kruppel-like factor 6. J Mol Med 95, 1191–1202 (2017). https://doi.org/10.1007/s00109-017-1586-5

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  • DOI: https://doi.org/10.1007/s00109-017-1586-5

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