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

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 beta 1 (TGF beta 1)-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 TGF beta 1 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 TGF beta 1. Six1 overexpression promoted an EMT-like phenotype with a decreased protein expression of E-cadherin and increased protein expression of alpha-smooth muscle actin (alpha-SMA) as well as fibronectin in 16HBE cells; these effects appeared to promote TGF beta 1 and phospho-Smad2 (pSmad2) production, which are the main products of the TGF beta 1/Smad signalling pathway, which could be reduced by a TGF beta 1 inhibitor. Conclusion: These data reveal that Six1 and TGF beta 1 are potentially a part of an autocrine feedback loop that induces EMT, and these factors can be reduced by blocking the TGF beta 1/Smad signalling pathway. As such, these factors may represent a promising novel therapeutic target for airway remodelling in asthma. (c) 2021 S. Karger AG, Basel

Automated summary

The study reveals that Six1 and TGFβ1 may be part of an autocrine feedback loop inducing EMT, which can be reduced by blocking the TGFβ1/Smad signaling pathway. These factors represent a promising novel therapeutic target for airway remodelling in asthma.