Identification of transforming growth factors actively transcribed during the progress of liver fibrosis in biliary atresia

Lee, Shin-Ye; Chuang, Jiin‐Haur; Huang, Chao‐Cheng; Chou, Ming-Huei; Wu, Chia‐Ling; Chen, Ching-Mei; Hsieh, Chie-Song; Chen, Chao‐Long

doi:10.1016/j.jpedsurg.2004.01.030

Cited by 25 publications

(18 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…49 In addition, TGF-␤2 has been shown to play an essential role in the development of tumors by regulation of key mechanisms including immunosuppression, 50-52 metastasis, 52 angiogenesis, 51 and cell growth and differentiation 46 and is thought to function as an important me- diator in the development of liver fibroses. 53 The expression of TGF-␤s has been reported, in liver tissues of patients infected with HCV, 19 and we confirmed this also in the current study. Thus, the contribution of TGF-␤2 in the modulation of HCV-associated hepatic angiogenesis is considered.…”

Section: Discussionsupporting

confidence: 91%

Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways

et al. 2009

View full text Add to dashboard Cite

Chronic hepatitis C virus (HCV) infection is associated with the production of serum cytokines, including transforming growth factor (TGF)-␤2. Despite the occurrence of hepatic angiogenesis in liver conditions, the role of HCV proteins in this context is currently unknown. We demonstrated that the development of hepatic neoangiogenesis in patients infected with HCV is associated with the expression of TGF-␤2 and vascular endothelial growth factor (VEGF) and with activation of endothelial cells, as evidenced by CD34 expression. The analysis of liver biopsies of HCV-positive and HCV-negative patients using immunostaining showed significant elevation of TGF-␤2, VEGF, and CD34 expression in patients who were HCV-positive. Using an HCV established culture system, we confirmed further the production of both TGF-␤2 and VEGF proteins, in the hepatoma cell lines HepG2 and Huh7 by transfection with full-length HCV RNA (JFH1) or by the regulated expression of core. In addition, regulated expression of core protein in HepG2 or Huh7 cells was found to induce expression and activation of the transcription factor E2F1 and apoptosis signal-regulating kinase 1 (ASK1), activation of c-jun-N-terminal kinase (JNK) and p38, and extracellular-regulated kinase (ERK), and transcription factors activator protein 1 (AP-1), activating transcription factor 2 (ATF-2), cyclic adenosine monophosphate response element binding (CREB), E2F1, hypoxia inducing factor 1 alpha (HIF-1␣), and specificity protein 1. Furthermore, data obtained from inhibitor experiments revealed the importance of E2F1 and ASK1 in the modulation of core-induced activation of JNK and p38 pathways and suggested an essential role for JNK, p38, and ERK pathways in the regulation of core-induced production of TGF-␤2 and VEGF proteins. Thus, our data provide insight into the molecular mechanisms whereby core protein mediates the development of hepatic angiogenesis in patients with chronic HCV infection.

show abstract

Section: Discussionsupporting

confidence: 91%

Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways

et al. 2009

View full text Add to dashboard Cite

show abstract

“…TGF-β2 secretion by activated rat portal fibroblasts is also increased both in isolated cells in vitro and in biliary atresia [30,34]. TGF-β has been shown to drive EMT in many in vivo and in vitro systems and likely also does so in the liver [2].…”

Section: Discussionmentioning

confidence: 98%

“…In biliary atresia, it has been well documented that there is increased production of TGF-β, particularly the isoform TGF-β2, by BECs and surrounding cells in cases with a prominent ductular reaction [28][29][30][31][32][33]. TGF-β2 secretion by activated rat portal fibroblasts is also increased both in isolated cells in vitro and in biliary atresia [30,34].…”

Section: Discussionmentioning

confidence: 99%

Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis

et al. 2008

View full text Add to dashboard Cite

“…For example, TGF-β2 contributes to cell proliferation and α-SMA expression in myofibroblasts [40]. Recently, TGF-β2 has been demonstrated to have a pro-fibrotic role in liver and kidney fibrosis [41,42]. Further study showed that TGF-β2 can be induced by TGF-β1 in HSCs [43].…”

Section: Discussionmentioning

confidence: 99%

The Epigenetically-Regulated microRNA-378a Targets TGF-β2 in TGF-β1-Treated Hepatic Stellate Cells

Yang

Huang³

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: In liver fibrosis, the activation of hepatic stellate cells (HSCs) is considered as a pivotal event. It is well known that transforming growth factor-β1 (TGF-β1) is the main stimuli factor responsible for HSC activation. microRNAs (miRNAs), regulating various biological processes, have recently been shown to be involved in HSC activation. A recent study reported that deficiency of miR-378a contributes to cardiac fibrosis via TGF-β1-dependent paracrine mechanism. However, the involvement of miR-378a and its roles in TGF-β1-induced HSC activation remains largely unknown. Methods: miR-378a expression was detected in TGF-β1-treated cells and patients with cirrhosis. Then, effects of miR-378a overexpression on cell proliferation and HSC activation were analyzed. We also analyzed the binding of miR-378a to the 3′-untranslated region of TGF-β2. Results: In response to TGF-β1, miR-378a expression was down-regulated in a dose-dependent manner. miR-378a overexpression suppressed both cell proliferation and cell cycle in TGF-β1-treated LX-2 cells. Moreover, miR-378a overexpression inhibited TGF-β1-induced HSC activation including the reduction of α-smooth muscle actin (α-SMA) and type I collagen. Similarly, miR-378a resulted in a reduction in cell proliferation, and the expressions of α-SMA and Col1A1 in TGF-β1-treated primary HSCs. Notably, TGF-β2 was confirmed as a target of miR-378a by luciferase reporter assays. Interestingly, miR-378a promoter methylation may be responsible for miR-378a down-regulation in TGF-β1-treated LX-2 cells and TGF-β1-treated primary HSCs. Further studies confirmed that reduced miR-378a was associated with promoter methylation in patients with cirrhosis compared with healthy controls. Conclusion: Our results demonstrate that miR-378a expression is associated with its methylation status in TGF-β1-treated cells, and epigenetically-regulated miR-378a inhibits TGF-β1-induced HSC activation, at least in part, via TGF-β2.

show abstract

Identification of transforming growth factors actively transcribed during the progress of liver fibrosis in biliary atresia

Cited by 25 publications

References 23 publications

Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways

Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways

Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis

The Epigenetically-Regulated microRNA-378a Targets TGF-β2 in TGF-β1-Treated Hepatic Stellate Cells

Contact Info

Product

Resources

About