MicroRNA-145 Induces the Senescence of Activated Hepatic Stellate Cells through the Activation of P53 Pathway by ZEB2
Abstract
Activation of quiescent hepatic stellate cells (HSCs) is the major event in liver fibrosis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. The p53, a guardian of the genome is associated with liver fibrosis, has been shown to regulate HSCs senescence. In this study, we report that microRNA‐145 (miR‐145) and p53 were downregulated in vivo and in vitro, concomitant with the enhanced expression of zinc finger E‐box binding homeobox 2 (ZEB2). In addition, overexpression of miR‐145 and p53 led to upregulation of the number of senescence‐associated β‐galactosidase‐positive HSCs and the expression of senescence markers p16 and p21, along with the reduced abundance of HSC activation markers α‐smooth muscle actin and type I collagen in activated HSCs. Furthermore, silencing of ZEB2 promoted senescence of activated HSCs. Moreover, we also demonstrated that miR‐145 specifically targeted the 3′‐untranslated regions of ZEB2. In vitro promoter regulation studies show that ZEB2 could bind to the E‐box of the p53 promoter as well as inhibit its promoter activity and thus suppress the expression of p53, which in turn repressed activated HSCs senescence. Taken together, our results describe a novel miR‐145‐ZEB2‐p53 regulatory line might participate in the senescence of activated HSCs and might carry potential therapeutic targets for restraining liver fibrosis.
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Downregulation of ZEB2 promotes cell senescence in hepatic stellate cells and dermal fibroblasts, limiting fibrosis.
“In support of this concept, there is evidence that the downregulation of the Zn-finger protein ZEB2 significantly promotes cell senescence in hepatic stellate cells and dermal fibroblasts, limiting the development of fibrosis [435,436].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [435]
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The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence
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Self-citation
- Authors
- Yang, J., Lu, Y., Yang, P., Chen, Q., Wang, Y., Ding, Q., Xu, T., Li, X., Li, C., Huang, C., Meng, X., Li, J., Zhang, L., & Wang, X.
- Affiliations
- Anhui Medical University (CN)
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University Hefei China
- First Affiliated Hospital of Anhui Medical University (CN)
- Corresponding author
- Zhang, Lei
- Wang, Xiao
- ORCID
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2018-11-27
- Volume
- 234
- Issue
- 5
- Pages
- 7587-7599
- ISSN
- 0021-9541 (ISSN-L)
- 1097-4652
- OpenAlex
- W2902605437
- Cited by
- 40
- References
- 46
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 7 · 2020: 4 · 2019: 4
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cellular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- The Anhui Natural Science Foundation (1608085MH234)
- This work was supported by the Intercollegiate Key Projects of Nature Science of Anhui Province (KJ2017A169), (KJ2014A124)
- Key Research Foundation of Higher Education of Anhui Province (gxfx2017011)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- miR-145, hepatic stellate cells, cellular senescence, liver fibrosis, p53, ZEB2, E-box binding, p16, p21, 3'-untranslated region targeting, alpha-smooth muscle actin, type I collagen
- MeSH terms
- Zinc Finger E-box Binding Homeobox 2, Animals, Cell Line, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Promoter Regions, Genetic, Signal Transduction, Down-Regulation, Up-Regulation, Tumor Suppressor Protein p53, Cellular Senescence, 3' Untranslated Regions, MicroRNAs, Cell Proliferation, Mice, Hepatic Stellate Cells
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