HOXC8/TGF-β1 positive feedback loop promotes liver fibrosis and hepatic stellate cell activation via activating Smad2/Smad3 signaling
Copyright © 2023 Elsevier Inc. All rights reserved..
Liver fibrosis occurs in any chronic liver disease, where extraordinary increase of extracellular matrix components is caused by the hepatic stellate cell (HSC) activation. HOXC8 has been disclosed to participate inregulating cell proliferation and fibrosis in tumors. However, the role of HOXC8 in liver fibrosis and the underlying molecular mechanisms has not yet been investigated. In this study, we founded that HOXC8 mRNA and protein was elevated in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model and transforming growth factor-β (TGF-β)-treated human (LX-2) HSC cells. Importantly, we observed that downregulating HOXC8 alleviates liver fibrosis and suppressed the fibrogenic gene induction induced by CCl4 in vivo. In addition, inhibition of HOXC8 suppressed the HSC activation and the expression of fibrosis-associated genes (α-SMA and COL1a1) induced by TGF-β1 in LX-2 cells in vitro, while HOXC8 overexpression had the opposite effects. Mechanistically, we demonstrated HOXC8 activates TGFβ1 transcription and enhanced the phosphorylated Smad2/Smad3 levels, suggesting a positive feedback loop between HOXC8 and TGF-β1 that facilitates TGF-β signaling and subsequent HSCs activation. Collectively, our data strongly indicated that a HOXC8/TGF-β1 positive feedback loop plays as a critical role in controlling the HSC activation and in the liver fibrosis process, suggesting that inhibition of HOXC8 may serve as a promoting therapeutic strategy for diseases characterized by liver fibrosis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:662 |
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| Enthalten in: |
Biochemical and biophysical research communications - 662(2023) vom: 25. Juni, Seite 39-46 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Ning [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.05.2023 Date Revised 12.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bbrc.2023.04.011 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a Liver fibrosis occurs in any chronic liver disease, where extraordinary increase of extracellular matrix components is caused by the hepatic stellate cell (HSC) activation. HOXC8 has been disclosed to participate inregulating cell proliferation and fibrosis in tumors. However, the role of HOXC8 in liver fibrosis and the underlying molecular mechanisms has not yet been investigated. In this study, we founded that HOXC8 mRNA and protein was elevated in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model and transforming growth factor-β (TGF-β)-treated human (LX-2) HSC cells. Importantly, we observed that downregulating HOXC8 alleviates liver fibrosis and suppressed the fibrogenic gene induction induced by CCl4 in vivo. In addition, inhibition of HOXC8 suppressed the HSC activation and the expression of fibrosis-associated genes (α-SMA and COL1a1) induced by TGF-β1 in LX-2 cells in vitro, while HOXC8 overexpression had the opposite effects. Mechanistically, we demonstrated HOXC8 activates TGFβ1 transcription and enhanced the phosphorylated Smad2/Smad3 levels, suggesting a positive feedback loop between HOXC8 and TGF-β1 that facilitates TGF-β signaling and subsequent HSCs activation. Collectively, our data strongly indicated that a HOXC8/TGF-β1 positive feedback loop plays as a critical role in controlling the HSC activation and in the liver fibrosis process, suggesting that inhibition of HOXC8 may serve as a promoting therapeutic strategy for diseases characterized by liver fibrosis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a HOXC8 | |
| 650 | 4 | |a Hepatic stellate cell activation | |
| 650 | 4 | |a Liver fibrosis | |
| 650 | 4 | |a Smad2/Smad3 | |
| 650 | 4 | |a TGF-β1 | |
| 650 | 7 | |a Transforming Growth Factor beta1 |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta |2 NLM | |
| 650 | 7 | |a Carbon Tetrachloride |2 NLM | |
| 650 | 7 | |a CL2T97X0V0 |2 NLM | |
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| 650 | 7 | |a Smad3 Protein |2 NLM | |
| 650 | 7 | |a HOXC8 protein, human |2 NLM | |
| 650 | 7 | |a Homeodomain Proteins |2 NLM | |
| 650 | 7 | |a SMAD2 protein, human |2 NLM | |
| 650 | 7 | |a Smad2 Protein |2 NLM | |
| 700 | 1 | |a Guo, Fang |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Yuanyuan |e verfasserin |4 aut | |
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