Abstract
Asbestos exposure increases the risk of asbestosis and malignant mesothelioma (MM). Both fibrosis and cancer have been correlated with the Epithelial to Mesenchymal Transition (EMT)—an event involved in fibrotic development and cancer progression. During EMT, epithelial cells acquire a mesenchymal phenotype by modulating some proteins. Different factors can induce EMT, but Transforming Growth Factor β (TGF-β) plays a crucial role in promoting EMT. In this work, we verified if EMT could be associated with MM development. We explored EMT in human mesothelial cells (MeT-5A) exposed to chrysotile asbestos: we demonstrated that asbestos induces EMT in MeT-5A cells by downregulating epithelial markers E-cadherin, β-catenin, and occludin, and contemporarily, by upregulating mesenchymal markers fibronectin, α-SMA, and vimentin, thus promoting EMT. In these cells, this mechanism is mediated by increased TGF-β secretion, which in turn downregulates E-cadherin and increases fibronectin. These events are reverted in the presence of TGF-β antibody, via a Small Mother Against Decapentaplegic (SMAD)-dependent pathway and its downstream effectors, such as Zinc finger protein SNAI1 (SNAIL-1), Twist-related protein (Twist), and Zinc Finger E-Box Binding Homeobox 1 (ZEB-1), which downregulate the E-cadherin gene. Since SNAIL-1, Twist, and ZEB-1 have been shown to be overexpressed in MM, these genes could be considered possible predictive or diagnostic markers of MM development.
Highlights
Asbestos is the common name for a group of hydrated fibrous silicates, whose exposure has been held responsible for a large number of lung diseases, such as asbestosis, lung cancer, and malignant mesothelioma (MM) [1]
Both pulmonary fibrosis and tumors have been associated with the ability of epithelial cells to become mesenchymal cells through a process known as Epithelial to Mesenchymal Transition (EMT)
In our previous work [20], we demonstrated that SNAIL-1 factor, in bronchial BEAS-2B cells exposed to chrysotile, is crucial in downregulating E-cadherin when it is accumulated into the nucleus, and this mechanism is mediated by a GSK-3β-dependent mechanism [26]
Summary
Asbestos is the common name for a group of hydrated fibrous silicates, whose exposure has been held responsible for a large number of lung diseases, such as asbestosis (a form of asbestos-induced fibrosis), lung cancer, and malignant mesothelioma (MM) [1]. In our previous work [20], we demonstrated that SNAIL-1 factor, in bronchial BEAS-2B cells exposed to chrysotile, is crucial in downregulating E-cadherin when it is accumulated into the nucleus, and this mechanism is mediated by a GSK-3β-dependent mechanism [26]. We observed that all these factors were strongly activated or overexpressed after asbestos exposure in MeT-5A cells Among these factors, transcription factor SNAIL-1 was associated in our previous work with EMT, and SNAIL-1 was in turn implicated in E-cadherin gene downregulation, as demonstrated [20]. With the present data, we demonstrated for the first time that chrysotile asbestos induces EMT in MeT-5A cells with a molecular mechanism involving TGF-β and its intracellular effectors, GSK-3β and SNAIL-1. The mechanism proposed can be considered as just one of the possible molecular mechanisms supporting the morphological transformations typical of EMT involved in MM development
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