scholarly journals TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition

2016 ◽  
Vol 38 (2) ◽  
pp. 571-588 ◽  
Author(s):  
Min-Jin Kim ◽  
Sang-A Park ◽  
Chun Hwa Kim ◽  
So-Yeon Park ◽  
Jung-Shin Kim ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Rat Model ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Type I ◽  
Receptor Kinase ◽  
Mesenchymal Transition ◽  
Duct Ligation

Background/Aims: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1α activates hepatic stellate cells (HSCs) and increases transforming growth factor-β (TGF-β) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197, on HIF1α-derived TGF-β signaling in cholestatic liver fibrosis. Methods: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-β signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. Results: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. Conclusion: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-β signaling.

scholarly journals TGFβ signaling regulates epithelial–mesenchymal plasticity in ovarian cancer ascites-derived spheroids

2015 ◽  
Vol 23 (3) ◽  
pp. 147-159 ◽  
Author(s):  
Samah Rafehi ◽  
Yudith Ramos Valdes ◽  
Monique Bertrand ◽  
Jacob McGee ◽  
Michel Préfontaine ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Type I ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Cancer Pathogenesis

Epithelial–mesenchymal transition (EMT) serves as a key mechanism driving tumor cell migration, invasion, and metastasis in many carcinomas. Transforming growth factor-beta (TGFβ) signaling is implicated in several steps during cancer pathogenesis and acts as a classical inducer of EMT. Since epithelial ovarian cancer (EOC) cells have the potential to switch between epithelial and mesenchymal states during metastasis, we predicted that modulation of TGFβ signaling would significantly impact EMT and the malignant potential of EOC spheroid cells. Ovarian cancer patient ascites-derived cells naturally underwent an EMT response when aggregating into spheroids, and this was reversed upon spheroid re-attachment to a substratum. CDH1/E-cadherin expression was markedly reduced in spheroids compared with adherent cells, in concert with an up-regulation of several transcriptional repressors, i.e., SNAI1/Snail, TWIST1/2, and ZEB2. Treatment of EOC spheroids with the TGFβ type I receptor inhibitor, SB-431542, potently blocked the endogenous activation of EMT in spheroids. Furthermore, treatment of spheroids with SB-431542 upon re-attachment enhanced the epithelial phenotype of dispersing cells and significantly decreased cell motility and Transwell migration. Spheroid formation was significantly compromised by exposure to SB-431542 that correlated with a reduction in cell viability particularly in combination with carboplatin treatment. Thus, our findings are the first to demonstrate that intact TGFβ signaling is required to control EMT in EOC ascites-derived cell spheroids, and it promotes the malignant characteristics of these structures. As such, we show the therapeutic potential for targeted inhibition of this pathway in ovarian cancer patients with late-stage disease.

scholarly journals TGF-β and the Smad Signaling Pathway Support Transcriptomic Reprogramming during Epithelial-Mesenchymal Cell Transition

2005 ◽  
Vol 16 (4) ◽  
pp. 1987-2002 ◽  
Author(s):  
Ulrich Valcourt ◽  
Marcin Kowanetz ◽  
Hideki Niimi ◽  
Carl-Henrik Heldin ◽  
Aristidis Moustakas
Keyword(s):  
Target Genes ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Type I ◽  
Mesenchymal Transition ◽  
Smad Signaling

Epithelial-mesenchymal transition (EMT) contributes to normal tissue patterning and carcinoma invasiveness. We show that transforming growth factor (TGF)-β/activin members, but not bone morphogenetic protein (BMP) members, can induce EMT in normal human and mouse epithelial cells. EMT correlates with the ability of these ligands to induce growth arrest. Ectopic expression of all type I receptors of the TGF-β superfamily establishes that TGF-β but not BMP pathways can elicit EMT. Ectopic Smad2 or Smad3 together with Smad4 enhanced, whereas dominant-negative forms of Smad2, Smad3, or Smad4, and wild-type inhibitory Smad7, blocked TGF-β–induced EMT. Transcriptomic analysis of EMT kinetics identified novel TGF-β target genes with ligand-specific responses. Using a TGF-β type I receptor that cannot activate Smads nor induce EMT, we found that Smad signaling is critical for regulation of all tested gene targets during EMT. One such gene, Id2, whose expression is repressed by TGF-β1 but induced by BMP-7 is critical for regulation of at least one important myoepithelial marker, α-smooth muscle actin, during EMT. Thus, based on ligand-specific responsiveness and evolutionary conservation of the gene expression patterns, we begin deciphering a genetic network downstream of TGF-β and predict functional links to the control of cell proliferation and EMT.

scholarly journals TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1419 ◽  
Author(s):  
Dewidar ◽  
Meyer ◽  
Dooley ◽  
Meindl-Beinker
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Stellate Cell ◽  
Reactive Oxygen Species Generation ◽  
Mesenchymal Transition ◽  
Therapeutic Benefits ◽  
Liver Fibrogenesis

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

scholarly journals Cholangiocyte proliferation and liver fibrosis

2009 ◽  
Vol 11 ◽  
Author(s):  
Shannon S. Glaser ◽  
Eugenio Gaudio ◽  
Tim Miller ◽  
Domenico Alvaro ◽  
Gianfranco Alpini
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Proliferative Response ◽  
Epithelial Mesenchymal Transition ◽  
Extrahepatic Bile Duct ◽  
In Vivo Model ◽  
Ductular Reaction ◽  
Mesenchymal Transition ◽  
Paracrine Signalling ◽  
Duct Ligation

Cholangiocyte proliferation is triggered during extrahepatic bile duct obstruction induced by bile duct ligation, which is a common in vivo model used for the study of cholangiocyte proliferation and liver fibrosis. The proliferative response of cholangiocytes during cholestasis is regulated by the complex interaction of several factors, including gastrointestinal hormones, neuroendocrine hormones and autocrine or paracrine signalling mechanisms. Activation of biliary proliferation (ductular reaction) is thought to have a key role in the initiation and progression of liver fibrosis. The first part of this review provides an overview of the primary functions of cholangiocytes in terms of secretin-stimulated bicarbonate secretion – a functional index of cholangiocyte growth. In the second section, we explore the important regulators, both inhibitory and stimulatory, that regulate the cholangiocyte proliferative response during cholestasis. We discuss the role of proliferating cholangiocytes in the induction of fibrosis either directly via epithelial mesenchymal transition or indirectly via the activation of other liver cell types. The possibility of targeting cholangiocyte proliferation as potential therapy for reducing and/or preventing liver fibrosis, and future avenues for research into how cholangiocytes participate in the process of liver fibrogenesis are described.

scholarly journals Inhibition of Pulmonary and Skeletal Metastasis by a Transforming Growth Factor-β Type I Receptor Kinase Inhibitor

2006 ◽  
Vol 66 (13) ◽  
pp. 6714-6721 ◽  
Author(s):  
Abhik Bandyopadhyay ◽  
Joseph K. Agyin ◽  
Long Wang ◽  
Yuping Tang ◽  
Xiufen Lei ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Skeletal Metastasis ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Receptor Kinase

scholarly journals The Anti-fibrotic Effect of Human Fetal Skin-derived Stem Cell Secretome on the Liver Fibrosis

2020 ◽  
Author(s):  
Xia Yao ◽  
Jing Wang ◽  
Jiajing Zhu ◽  
Xiaoli Rong
Keyword(s):  
Stem Cells ◽  
Liver Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Fetal Skin ◽  
Mesenchymal Transition ◽  
Cell Based Therapy ◽  
Causes Of Mortality ◽  
Smad7 Expression

Abstract Background: Liver fibrosis resulting from chronic liver injury is one of the major causes of mortality worldwide. Stem cells-secreted secretome has been evaluated for overcoming the limitations of cell-based therapy in hepatic disease, while maintaining its advantages.Methods: In this study, we investigated the effect ofhuman fetal skin-derived stem cells (hFFSCs) secretome in the treatment of liver fibrosis. To determine the therapeutic potential of the hFFSCssecretome in liver fibrosis, we established the CCl4-induced rat liver fibrosis model, and administered hFFSCssecretome in vivo. Moreover, we investigated the anti-fibrotic mechanism of hFFSCssecretome in hepatic stellate cells (HSCs).Results: Our results showed that hFFSCssecretomeffectively reduced collagen content in liver, improved the liver function and promoted liver regeneration. Interestingly, we also found thathFFSCssecretom reduced liver fibrosis through suppressing the epithelial-mesenchymal transition (EMT) process. In addition, we found that hFSSCsecretom inhibited the TGF-β1, Smad2, Smad3, and Collagen I expression, however, increased Smad7 expression.Conclusions: In conclusions, our results suggest that hFFSCssecretome treatment could reduce CCl4-induced liver fibrosis via regulating the TGF-β/Smad signal pathway.

Human fetal skin-derived stem cell secretome reduce liver fibrosis

2020 ◽  
Author(s):  
Xia Yao ◽  
Jing Wang ◽  
Jiajing Zhu ◽  
Xiaoli Rong
Keyword(s):  
Stem Cells ◽  
Liver Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Fetal Skin ◽  
Mesenchymal Transition ◽  
Cell Based Therapy ◽  
Current Therapies ◽  
Causes Of Mortality

Abstract Background: Liver fibrosis resulting from a chronic liver injury is one of the significant causes of mortality. Stem cells-secreted secretome has been evaluated for overcoming the limitations of cell-based therapy in hepatic disease while maintaining its advantages over the current therapies. Methods: In this study, we investigated the effect of human fetal skin-derived stem cells (hFSSCs) secretome in the treatment of liver fibrosis. To determine the therapeutic potential of the hFSSCs secretome in liver fibrosis, we established the CCl4-induced liver fibrosis rat model, and we administered hFSSCs secretome in vivo. Moreover, we investigated the anti-fibrotic mechanism of hFSSCs secretome in hepatic stellate cells (HSCs). Results: Our results showed that hFSSCs secretome effectively reduced collagen content in the liver, and improved the liver function and promoted liver regeneration. Interestingly, we also found that hFSSCs secretome reduced liver fibrosis through suppressing the epithelial-mesenchymal transition (EMT) process. In addition, we found that hFSSC secretome inhibited the TGF-β1, Smad2, Smad3, and Collagen I expression, while we observed, increased Smad7 expression. Conclusions: In conclusion, our results suggest that hFSSCs secretome treatment could reduce CCl4-induced liver fibrosis via regulating the TGF-β/Smad signal pathway.

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