Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-β as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event

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.

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

“…Many genes associated with reprogramming of cell–cell and cell–extracellular matrix interactions orchestrated by means of the EMT process are differentially expressed in MPM and correlate with worse survival. Interestingly, a substantial number of these genes such as matrix metalloproteases ( MMP3 , MMP7 , and MMP14 ), integrins, and a group of cytoskeletal proteins and cell adhesion molecules ( ITGA3 , ITGB4 , VCAN , VIM , PECAM1 , CDH1 , CDH5 , and CD44 ), structural molecules, and modifiers of ECM ( LOXL2 , BNC1 , GREM-1 , FBN2 , THBS2 , RASGRP3 , ANXA6 , ADAMTS6 , and ADAM19 ) and transcription factors ( SNAI1 , SNAI2 , ZEB1 , TWIST1 , and HMGA2 ) are either significantly enriched in the gene signature or recognized as signaling modulators of the TGF-β (transforming growth factor β) pathway [ 19 , 62 , 112 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ]. Indeed, a large body of evidence that accumulated over the last few years, suggests that the TGF-β signaling pathway is dysregulated in MPM.…”

“…Indeed, a large body of evidence that accumulated over the last few years, suggests that the TGF-β signaling pathway is dysregulated in MPM. Thereof, a less favorable prognostic association has been identified between the EMT score of MPM and the activated TGF-β gene signature [ 119 , 123 ]. Taken together, further studies may provide the basis for assessing TGF-β pathway-specific inhibitors for targeted therapy in MPM, at least in those with high EMT scores.…”

Polydatin ameliorates pulmonary fibrosis by suppressing inflammation and the epithelial mesenchymal transition via inhibiting the TGF-β/Smad signaling pathway

“…TGFb plays a crucial role in promoting EMT. 20 TGF-b was used to induce brosis of HFL-1 cells. The results showed that TGFb promoted migration of HFL-1 cells compared with control group.…”

Hollow Alginate-Poly-L-Lysine-Alginate Microspheres Promoted an Epithelial-Mesenchymal Transition in Human Colon Adenocarcinoma Cells

“…To monitor the potency of encapsulation on EMT and stemness acquisition, we also performed real-time PCR analysis. 17 Data showed that the expression of three genes Snail, Vimentin and Zeb were increased 7 days after encapsulation of HT-29 cells with Alg and PLL compared to the control cells expanded on the plastic surface (P < 0.05; Figure 2b). Of note, the use of Alg microspheres loaded with PLL could significantly upregulate all genes (Figure 2b).…”