scholarly journals Six1 Promotes Epithelial-Mesenchymal Transition in Bronchial Epithelial Cells via the TGFβ1/Smad Signalling Pathway

2021 ◽  
pp. 1-10
Author(s):  
Wenxin Wang ◽  
Zhaochuan Yang ◽  
Meixiang Li ◽  
Zhenhong Wang ◽  
Yanchun Shan ◽  
...  
Keyword(s):  
Mouse Model ◽  
Protein Expression ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Signalling Pathway ◽  
Expression Vectors ◽  
Airway Remodelling ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition

Introduction: The homeodomain transcription factor sine oculis homeobox homolog 1 (Six1) plays a crucial role in embryogenesis and is not expressed in normal adult tissue but is expressed in many pathological processes, including airway remodelling in asthma. The current study aimed to reveal the effects of Six1 in regulating the airway remodelling and its possible mechanism. Methods: A mouse model of ovalbumin-induced asthma-associated airway wall remodelling and a bronchial epithelial cell (16HBE) model of transforming growth factor β1 (TGFβ1)-induced epithelial-mesenchymal transition (EMT) were used to investigate the role of Six1. Then, 16HBE cells were transformed with Six1 expression vectors and treated with a TGFβ1 pathway inhibitor to determine the role of Six1 in EMT. The effect of Six1 and its possible mechanism were assessed by immunohistochemistry, RT-PCR, and Western blot. Results: Six1 expression was elevated in the lungs in an OVA mouse model of allergic asthma and in 16HBE cells treated with TGFβ1. Six1 overexpression promoted an EMT-like phenotype with a decreased protein expression of E-cadherin and increased protein expression of α-smooth muscle actin (α-SMA) as well as fibronectin in 16HBE cells; these effects appeared to promote TGFβ1 and phospho-Smad2 (pSmad2) production, which are the main products of the TGFβ1/Smad signalling pathway, which could be reduced by a TGFβ1 inhibitor. Conclusion: These data reveal that Six1 and TGFβ1 are potentially a part of an autocrine feedback loop that induces EMT, and these factors can be reduced by blocking the TGFβ1/Smad signalling pathway. As such, these factors may represent a promising novel therapeutic target for airway remodelling in asthma.

scholarly journals Death-Associated Protein 6 (Daxx) Alleviates Liver Fibrosis by Modulating Smad2 Acetylation

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1742
Author(s):  
Sung-Min Kim ◽  
Won-Hee Hur ◽  
Byung-Yoon Kang ◽  
Sung-Won Lee ◽  
Pu-Reun Roh ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Mouse Model ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Apoptotic Pathway ◽  
Mesenchymal Transition ◽  
Pathway Activation

Transforming growth factor-β (TGF-β) has been identified as an inducer of hepatocyte epithelial–mesenchymal transition (EMT), which triggers liver fibrosis. Death-associated protein 6 (Daxx) is known to be associated with the TGF-β-induced apoptotic pathway, but the function of Daxx in liver fibrosis remains unknown. This study aimed to elucidate the role of Daxx in liver fibrosis. We used liver fibrosis tissues from humans and mice to assess Daxx expression. EMT properties and TGF-β signaling pathway activation were investigated in the Daxx-overexpressing FL83B cell line. The therapeutic effect of Daxx was investigated in a mouse model of liver fibrosis by the hydrodynamic injection of plasmids. The expression of Daxx was markedly decreased in hepatocytes from fibrotic human and mouse livers, as well as in hepatocytes treated with TGF-β in vitro. The overexpression of Daxx inhibited the EMT process by interfering with the TGF-β-induced phosphorylation of Smad2. Coimmunoprecipitation analysis confirmed that Daxx reduced the transcriptional activity of Smad2 by binding to its MH1 domain and interfering with Smad2 acetylation. In addition, the therapeutic delivery of Daxx alleviated liver fibrosis in a thioacetamide-induced fibrosis mouse model. Overall, our results indicate that Daxx could be a potential therapeutic target to modulate fibrogenesis, as well as a useful biomarker for liver fibrosis.

scholarly journals TGF-β Signaling and the Epithelial-Mesenchymal Transition during Palatal Fusion

2018 ◽  
Vol 19 (11) ◽  
pp. 3638 ◽  
Author(s):  
Akira Nakajima ◽  
Charles F. Shuler ◽  
Alexander Gulka ◽  
Jun-ichi Hanai
Keyword(s):  
Cell Fate ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Genetically Engineered ◽  
Fusion Process ◽  
Mesenchymal Transition ◽  
Morphological Process ◽  
Palatal Fusion ◽  
Genetically Engineered Mice

Signaling by transforming growth factor (TGF)-β plays an important role in development, including in palatogenesis. The dynamic morphological process of palatal fusion occurs to achieve separation of the nasal and oral cavities. Critically and specifically important in palatal fusion are the medial edge epithelial (MEE) cells, which are initially present at the palatal midline seam and over the course of the palate fusion process are lost from the seam, due to cell migration, epithelial-mesenchymal transition (EMT), and/or programed cell death. In order to define the role of TGF-β signaling during this process, several approaches have been utilized, including a small interfering RNA (siRNA) strategy targeting TGF-β receptors in an organ culture context, the use of genetically engineered mice, such as Wnt1-cre/R26R double transgenic mice, and a cell fate tracing through utilization of cell lineage markers. These approaches have permitted investigators to distinguish some specific traits of well-defined cell populations throughout the palatogenic events. In this paper, we summarize the current understanding on the role of TGF-β signaling, and specifically its association with MEE cell fate during palatal fusion. TGF-β is highly regulated both temporally and spatially, with TGF-β3 and Smad2 being the preferentially expressed signaling molecules in the critical cells of the fusion processes. Interestingly, the accessory receptor, TGF-β type 3 receptor, is also critical for palatal fusion, with evidence for its significance provided by Cre-lox systems and siRNA approaches. This suggests the high demand of ligand for this fine-tuned signaling process. We discuss the new insights in the fate of MEE cells in the midline epithelial seam (MES) during the palate fusion process, with a particular focus on the role of TGF-β signaling.

Blocking core fucosylation of TGF-β1 receptors downregulates their functions and attenuates the epithelial-mesenchymal transition of renal tubular cells

2011 ◽  
Vol 300 (4) ◽  
pp. F1017-F1025 ◽  
Author(s):  
Hongli Lin ◽  
Dapeng Wang ◽  
Taihua Wu ◽  
Cui Dong ◽  
Nan Shen ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Interstitial Fibrosis ◽  
Cell Model ◽  
Mesenchymal Transition ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Core Fucosylation ◽  
Tgf Β1

Posttranslational modification of proteins could regulate their multiple biological functions. Transforming growth factor-β receptor I and II (ALK5 and TGF-βRII), which are glycoproteins, play important roles in the renal tubular epithelial-mesenchymal transition (EMT). In the present study, we examined the role of core fucosylation of TGF-βRII and ALK5, which is regulated by α-1,6 fucosyltransferase (Fut8), in the process of EMT of cultured human renal proximal tubular epithelial (HK-2) cells. The typical cell model of EMT induced by TGF-β1 was constructed to address the role of core fucosylation in EMT. Core fucosylation was found to be essential for both TGF-βRII and ALK5 to fulfill their functions, and blocking it with Fut8 small interfering RNA greatly reduced the phosphorylation of Smad2/3 protein, caused the inactivation of TGF-β/Smad2/3 signaling, and resulted in remission of EMT. More importantly, even with high levels of expressions of TGF-β1, TGF-βRII, and ALK5, blocking core fucosylation also could attenuate the EMT of HK-2 cells. Thus blocking core fucosylation of TGF-βRII and ALK5 may attenuate EMT independently of the expression of these proteins. This study may provide new insight into the role of glycosylation in renal interstitial fibrosis. Furthermore, core fucosylation may be a novel potential therapeutic target for treatment of renal tubular EMT.

TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease

2007 ◽  
Vol 293 (3) ◽  
pp. L525-L534 ◽  
Author(s):  
Brigham C. Willis ◽  
Zea Borok
Keyword(s):  
Epithelial Cells ◽  
Lung Disease ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Fibrotic Lung Disease

Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to fibrosis following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor (TGF)-β induces EMT in alveolar epithelial cells (AEC) in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II (AT2) cells in lung tissue from patients with idiopathic pulmonary fibrosis (IPF), suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to fibrosis in adult tissues following injury, focusing especially on the critical role of TGF-β and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of fibrotic lung disease. Treatment for fibrosis of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.

EPITHELIAL-MESENCHYMAL AND MESENCHYMAL-EPITHELIAL TRANSITION, PATHOGENESIS, REGULATION, THERAPY

2018 ◽  
Vol 64 (1) ◽  
pp. 62-72
Author(s):  
V. Shcherbakov ◽  
T. Ryabichenko ◽  
G. Skosyreva ◽  
A. Trunov
Keyword(s):  
Tumor Growth ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Anticancer Therapy ◽  
Lung Carcinogenesis ◽  
Mesenchymal Transition ◽  
Transforming Growth Factor ß1 ◽  
Mesenchymal Epithelial Transition

The review considered the issues of epithelial-mesenchymal transition (EMT) and its role in inflammation, fibrosis, tumor growth. There were analyzed mechanisms and classification of EMT. A comparison of different forms of EMTs was performed. The important role of EMT in the formation of metastasis-initiating cells was noted. There were presented data on the role of fibroblasts in fibrosis of the lung, carcinogenesis. Stimulators and inhibitors of EMTs were summarized. There were considered intracellular paths that were associated with the development of the EMT under the influence of transforming growth factor ß1 (TGF - ß1). It also induced the development of local hypothyroidism, for easy expression of oncofetal genes, which was especially important in tumor growth. Therapy EMT was associated with blocking the actions of TGF - ß1 and was an important area in anticancer therapy.

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