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Multi-walled carbon nanotubes directly induce epithelial-mesenchymal transition in human bronchial epithelial cells via the TGF-?-mediated Akt/GSK-3?/SNAIL-1 signalling pathway.

ABSTRACT:

Background

Multi-walled carbon nanotubes (MWCNT) are currently under intense toxicological investigation due to concern on their potential health effects. Current in vitro and in vivo data indicate that MWCNT exposure is strongly associated with lung toxicity (inflammation, fibrosis, granuloma, cancer and airway injury) and their effects might be comparable to asbestos-induced carcinogenesis. Although fibrosis is a multi-origin disease, epithelial-mesenchymal transition (EMT) is recently recognized as an important pathway in cell transformation. It is known that MWCNT exposure induces EMT through the activation of the TGF-?/Smad signalling pathway thus promoting pulmonary fibrosis, but the molecular mechanisms involved are not fully understood. In the present work we propose a new mechanism involving a TGF-?-mediated signalling pathway.

Methods

Human bronchial epithelial cells were incubated with two different MWCNT samples at various concentrations for up to 96 h and several markers of EMT were investigated. Quantitative real time PCR, western blot, immunofluorescent staining and gelatin zymographies were performed to detect the marker protein alterations. ELISA was performed to evaluate TGF-? production. Experiments with neutralizing anti-TGF-? antibody, specific inhibitors of GSK-3? and Akt and siRNA were carried out in order to confirm their involvement in MWCNT-induced EMT. In vivo experiments of pharyngeal aspiration in C57BL/6 mice were also performed. Data were analyzed by a one-way ANOVA with Tukey's post-hoc test.

Results

Fully characterized MWCNT (mean length?ConclusionsWe demonstrate a new molecular mechanism of MWCNT-mediated EMT, which is Smad-independent and involves TGF-? and its intracellular effectors Akt/GSK-3? that activate the SNAIL-1 signalling pathway. This finding suggests potential novel targets in the development of therapeutic and preventive approaches.

SUBMITTER: Polimeni M

PROVIDER: S-EPMC4890337 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Multi-walled carbon nanotubes directly induce epithelial-mesenchymal transition in human bronchial epithelial cells via the TGF-β-mediated Akt/GSK-3β/SNAIL-1 signalling pathway.

Polimeni Manuela M Gulino Giulia Rossana GR Gazzano Elena E Kopecka Joanna J Marucco Arianna A Fenoglio Ivana I Cesano Federico F Campagnolo Luisa L Magrini Andrea A Pietroiusti Antonio A Ghigo Dario D Aldieri Elisabetta E

Particle and fibre toxicology 20160601 1

<h4>Background</h4>Multi-walled carbon nanotubes (MWCNT) are currently under intense toxicological investigation due to concern on their potential health effects. Current in vitro and in vivo data indicate that MWCNT exposure is strongly associated with lung toxicity (inflammation, fibrosis, granuloma, cancer and airway injury) and their effects might be comparable to asbestos-induced carcinogenesis. Although fibrosis is a multi-origin disease, epithelial-mesenchymal transition (EMT) is recently ...[more]

PMID: 27251132

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