Igf2bp2 knockdown improves CCl4-induced liver fibrosis and TGF-β-activated mouse hepatic stellate cells by regulating Tgfbr1
Copyright © 2022 Elsevier B.V. All rights reserved..
Progressive liver fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix (ECM), which could eventually develop into cirrhosis, leading to malignant transformation. In this study, insulin-like growth factor 2 mRNA binding protein 2 (Igf2bp2) was found to be up-regulated in carbon tetrachloride (CCl4)-induced liver fibrosis and transforming growth factor-beta 1 (TGF-β)-activated hepatic stellate cells (HSCs). Igf2bp2 knockdown in the CCl4-induced hepatic fibrosis mice model significantly improved CCl4-induced liver damage by decreasing necrosis and fibrotic septa, reducing hydroxyproline levels, and down-regulating fibrotic markers levels. In TGF-β-activated HSCs, Igf2bp2 knockdown partially attenuated TGF-β-induced cellular effects by suppressing HSCs viability and DNA synthesis and reducing the ECM-associated factors such as α-SMA, COLLAGEN I, and COLLAGEN III. Integrative network and signaling analysis revealed that the Igf2bp2 could bind to Tgfbr1. Transforming growth factor-beta receptor 1 (Tgfbr1) was found to be significantly up-regulated in the fibrotic liver and activated HSCs, and positively correlated with Igf2bp2. Tgfbr1 knockdown partially eliminated TGF-β-induced fibrotic changes and Igf2bp2 overexpression effects on TGF-β-activated HSCs in vitro. Moreover, Igf2bp2 overexpression promoted the phosphorylation of SMAD2/SMAD3, AKT, and PI3K, whereas Tgfbr1 knockdown exhibited the opposite effect; Tgfbr1 knockdown also partially attenuated the effects of Igf2bp2 overexpression on the phosphorylation of SMAD2/SMAD3, AKT, and PI3K. In closing, Igf2bp2 and Tgfbr1 are up-regulated in CCl4-induced liver fibrosis and TGF-β-activated mHSCs. Igf2bp2 knockdown improved CCl4-induced liver fibrosis and TGF-β-activated HSCs by targeting Tgfbr1, possibly through the PI3K/Akt pathway.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:110 |
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| Enthalten in: |
International immunopharmacology - 110(2022) vom: 05. Sept., Seite 108987 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xu, Zhenyu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.08.2022 Date Revised 17.08.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.intimp.2022.108987 |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2022 Elsevier B.V. All rights reserved. | ||
| 520 | |a Progressive liver fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix (ECM), which could eventually develop into cirrhosis, leading to malignant transformation. In this study, insulin-like growth factor 2 mRNA binding protein 2 (Igf2bp2) was found to be up-regulated in carbon tetrachloride (CCl4)-induced liver fibrosis and transforming growth factor-beta 1 (TGF-β)-activated hepatic stellate cells (HSCs). Igf2bp2 knockdown in the CCl4-induced hepatic fibrosis mice model significantly improved CCl4-induced liver damage by decreasing necrosis and fibrotic septa, reducing hydroxyproline levels, and down-regulating fibrotic markers levels. In TGF-β-activated HSCs, Igf2bp2 knockdown partially attenuated TGF-β-induced cellular effects by suppressing HSCs viability and DNA synthesis and reducing the ECM-associated factors such as α-SMA, COLLAGEN I, and COLLAGEN III. Integrative network and signaling analysis revealed that the Igf2bp2 could bind to Tgfbr1. Transforming growth factor-beta receptor 1 (Tgfbr1) was found to be significantly up-regulated in the fibrotic liver and activated HSCs, and positively correlated with Igf2bp2. Tgfbr1 knockdown partially eliminated TGF-β-induced fibrotic changes and Igf2bp2 overexpression effects on TGF-β-activated HSCs in vitro. Moreover, Igf2bp2 overexpression promoted the phosphorylation of SMAD2/SMAD3, AKT, and PI3K, whereas Tgfbr1 knockdown exhibited the opposite effect; Tgfbr1 knockdown also partially attenuated the effects of Igf2bp2 overexpression on the phosphorylation of SMAD2/SMAD3, AKT, and PI3K. In closing, Igf2bp2 and Tgfbr1 are up-regulated in CCl4-induced liver fibrosis and TGF-β-activated mHSCs. Igf2bp2 knockdown improved CCl4-induced liver fibrosis and TGF-β-activated HSCs by targeting Tgfbr1, possibly through the PI3K/Akt pathway | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Hepatic fibrosis | |
| 650 | 4 | |a Igf2bp2 | |
| 650 | 4 | |a Mouse hepatic stellate cells (mHSCs) | |
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| 650 | 7 | |a Transforming Growth Factors |2 NLM | |
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| 700 | 1 | |a Jiang, Yongfang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yanwen |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Mengxuan |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Jiashi |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Feng |e verfasserin |4 aut | |
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