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TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells

Smoktunowicz, N; Platé, M; Ortiz-Stern, A; D'Antongiovanni, V; Robinson, E; Chudasama, V; Caddick, S; ... Chambers, RC; + view all (2016) TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells. Oncotarget , 7 (40) pp. 65471-65484. 10.18632/oncotarget.11472. Green open access

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Abstract

The major high-affinity thrombin receptor, proteinase activated receptor-1 (PAR-1) is expressed at low levels by the normal epithelium but is upregulated in many types of cancer, including lung cancer. The thrombin-PAR-1 signalling axis contributes to the activation of latent TGFβ in response to tissue injury via an αvβ6 integrin-mediated mechanism. TGFβ is a pleiotropic cytokine that acts as a tumour suppressor in normal and dysplastic cells but switches into a tumour promoter in advanced tumours. In this study we demonstrate that TGFβ is a positive regulator of PAR-1 expression in A549 lung adenocarcinoma cells, which in turn increases the sensitivity of these cells to thrombin signalling. We further demonstrate that this effect is Smad3-, ERK1/2- and Sp1-dependent. We also show that TGFβ-mediated PAR-1 upregulation is accompanied by increased expression of integrin αv and β6 subunits. Finally, TGFβ pre-stimulation promotes increased migratory potential of A549 to thrombin. These data have important implications for our understanding of the interplay between coagulation and TGFβ signalling responses in lung cancer.

Type: Article
Title: TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.18632/oncotarget.11472
Publisher version: http://dx.doi.org/10.18632/oncotarget.11472
Language: English
Additional information: Copyright © 2016 Impact Journals, LLC. All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License (CC BY 3.0) (https://creativecommons.org/licenses/by/3.0/)
Keywords: PAR-1, TGFβ, cancer, thrombin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1511279
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