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TGF-β1/Smad3 upregulates UCA1 to promote liver fibrosis through DKK1 and miR18a

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Abstract

TGF‐β1 is the strongest cytokine known to promote liver fibrosis. It has been previously demonstrated that the activation of TGF‐β1 initiates a temporary collagen accumulation program, which is important for wound repair in several organs. Furthermore, temporary extracellular matrix enhancement often leads to progressive fibrosis, which is accountable for cases of severe morbidity and mortality worldwide. However, its action mechanism has not been fully explored. It was previously reported that UCA1 could promote its occurrence and development in various tumors. Importantly, it was reported that TGF‐β1 could activate the expression of UCA1 in liver cancer, gastric cancer, and breast cancer. However, the role of UCA1 in organ fibrosis, including liver fibrosis, remains unreported. The present study reported for the first time that TGF‐β1/Smad3 could promote liver fibrosis by upregulating UCA1, which further affected DKK1 and collagen, such as COL1A1, COL1A2, and COL3A1. Meanwhile, UCA1 could competitively bind with miR18a to stabilize Smad3 to constitute a positive feedback pathway, which played a significant role in the promotion of liver fibrosis. Altogether, the present study provides a theoretical basis for devising promising treatment strategies for liver fibrosis.

Key messages

  • UCA1 was found to promote the progression of liver fibrosis in vitro.

  • UCA1 is regulated by TGF-β1 and promotes liver fibrosis through the canonical Smad pathway.

  • UCA1 can competitively bind with miR18a, promote liver fibrosis by stabilizing Smad3, and form a UCA1-miR18a/Smad3 positive feedback.

  • UCA1 binds EZH2 to inhibit the DKK1 expression and promote liver fibrosis.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by the National Natural Science Foundation of China (grant numbers 81770283, 82070302, 81902018, 81903001, and 81772926); Clinical Medical Research Center of Peritoneal Cancer of Wuhan (grant number 2015060911020462); Natural Science Foundation of Hubei Province (grant numbers 2019CFB109 and 2020CFB708); Technology and Innovation Seed Fund, Zhongnan Hospital of Wuhan University (grant number znpy2018004); and Medical Sci-Tech Innovation Platform, Zhongnan Hospital of Wuhan University (grant number PTXM2021022).

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Author notes

  1. Zhangshuo Yang and Hao Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, People’s Republic of China

    Zhangshuo Yang, Hao Zhang, Maohui Yin, Zhixiang Cheng, Ping Jiang, Zhisu Liu & Bo Liao

  2. Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, People’s Republic of China

    Maohui Feng

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Contributions

Conception and design: ZS.Y. and B.L.; development of methodology: ZS.Y., H.Z., and MH.Y.; acquisition of data: ZS.Y., MH.Y., ZX.C., and P.J.; analysis of data: ZS.Y., MH.F., B.L., and ZS.L.; writing, review, and/or revision of the manuscript: ZS.Y., H.Z., B.L., MH.F., and ZS.L. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Maohui Feng, Zhisu Liu or Bo Liao.

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The tissues collected in this paper have passed the ethical approval of Wuhan University Zhongnan Hospital. This study conforms to the ethical guidelines of the Declaration of Helsinki.

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Yang, Z., Zhang, H., Yin, M. et al. TGF-β1/Smad3 upregulates UCA1 to promote liver fibrosis through DKK1 and miR18a. J Mol Med 100, 1465–1478 (2022). https://doi.org/10.1007/s00109-022-02248-6

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