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Archives of Toxicology

, Volume 92, Issue 9, pp 2935–2946 | Cite as

MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis

  • Le Tao
  • Dongying Xue
  • Dongxiao Shen
  • Wenting Ma
  • Jie Zhang
  • Xuefei Wang
  • Wei Zhang
  • Liu Wu
  • Kai Pan
  • Yanqin Yang
  • Zeribe C. Nwosu
  • Steven Dooley
  • Ekihiro Seki
  • Cheng Liu
Organ Toxicity and Mechanisms
  • 233 Downloads

Abstract

MicroRNA (miRNA)-mediated gene regulation contributes to liver pathophysiology, including hepatic stellate cell (HSC) activation and fibrosis progression. Here, we investigated the role of miR-942 in human liver fibrosis. The expression of miR-942, HSC activation markers, transforming growth factor-beta pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI), as well as collagen deposition, were investigated in 100 liver specimens from patients with varying degree of hepatitis B virus (HBV)-related fibrosis. Human primary HSCs and the immortalized cell line (LX2 cells) were used for functional studies. We found that miR-942 expression was upregulated in activated HSCs and correlated inversely with BAMBI expression in liver fibrosis progression. Transforming growth factor beta (TGF-β) and lipopolyssacharide (LPS), two major drivers of liver fibrosis and inflammation, induce miR-942 expression in HSCs via Smad2/3 respective NF-κB/p50 binding to the miR-942 promoter. Mechanistically, the induced miR-942 degrades BAMBI mRNA in HSCs, thereby sensitizing the cells for fibrogenic TGF-β signaling and also partly mediates LPS-induced proinflammatory HSC fate. In conclusion, the TGF-β and LPS-induced miR-942 mediates HSC activation through downregulation of BAMBI in human liver fibrosis. Our study provides new insights on the molecular mechanism of HSC activation and fibrosis.

Keywords

TGF-β signaling HSCs Viral hepatitis Liver fibrosis 

Abbreviations

α-SMA

α-Smooth muscle actin

BAMBI

BMP and activin membrane-bound inhibitor

BSA

Bovine serum albumin

ChIP

Chromatin immunoprecipitation

ECM

Extracellular matrix

HSC

Hepatic stellate cell

hHSC

Primary human HSC

KCs

Kupffer cells

LPS

Lipopolysaccharide

LSECs

Liver sinusoidal endothelial cells

mRNA

Messenger RNA

PBS

Phosphate-buffered saline

TGFβ

Transforming growth factor β

UTR

Untranslated regions

Notes

Acknowledgements

This work was mainly supported by The National Natural Science Foundation of China (No. 81673788 to C. Liu), Peak discipline of Colleges and universities in Shanghai (No. A-U151902 to C Liu), and Research Project of Putuo Hospital Fund (No. 2016204B to C Liu & No. 2017207A to WT M). Federal Ministry of Education and Research grant ‘LiSyM’ (Grant PTJ-FKZ: 031L0043 to S Dooley). National Institutes of Health Grant (No. R01DK085252, R21AA025841 to E. Seki) and Winnick Research award from Cedars-Sinai Medical Center (to E. Seki). Xinglin Scholar of Shanghai University of Traditional Chinese Medicine (to C Liu) and Shanghai Municipal Commission of Health and Family Plan Fund (No. 20144Y0185 to L Wu). We thank Lingzhi Lian and honghui Wen (Department of Pathology, Putuo Hospital) for technical support with fibrotic stage analysis.

Author contributions

CL, ES and SD conceived and designed the experiments, and discussed the results. LT, DXS and WTM carried out all experiments. XFW, YQY, LW, KP, DYX and ZJ helped with the human liver biopsy specimen. ZCN supported with data presentation and in manuscript revision. CL and ES wrote the manuscript, which was read, edited and approved by all the authors.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2018_2278_MOESM1_ESM.docx (315 kb)
Supplementary material 1 (DOCX 315 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Central Laboratory, Putuo HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
  2. 2.Laboratory of Liver Disease, Department of Infectious Disease, Putuo HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
  3. 3.Department of Pathology, Putuo HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
  4. 4.Department of Medicine II, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
  5. 5.Division of Digestive and Liver Diseases, Department of MedicineCedars-Sinai Medical CenterLos AngelesUSA
  6. 6.Shanghai Putuo Central School of Clinical MedicineAnhui Medical UniversityShanghaiChina

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