dc.contributor.author | Smoktunowicz, N | |
dc.contributor.author | Platé, M | |
dc.contributor.author | Ortiz-Stern, A | |
dc.contributor.author | D'Antongiovanni, V | |
dc.contributor.author | Robinson, E | |
dc.contributor.author | Chudasama, V | |
dc.contributor.author | Caddick, S | |
dc.contributor.author | Scotton, CJ | |
dc.contributor.author | Jarai, G | |
dc.contributor.author | Chambers, RC | |
dc.date.accessioned | 2016-10-21T11:55:03Z | |
dc.date.issued | 2016-08-22 | |
dc.description.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. | en_GB |
dc.description.sponsorship | Medical Research Council UK (MRC) CASE studentship with Novartis awarded to RCC, MRC Centenary Award awarded to NS and RCC, and MRC Career Development Award G0800340 to CJS. | en_GB |
dc.identifier.citation | Vol. 7, No. 40, pp. 65471-65484. | en_GB |
dc.identifier.doi | 10.18632/oncotarget.11472 | |
dc.identifier.uri | http://hdl.handle.net/10871/24011 | |
dc.language.iso | en | en_GB |
dc.publisher | Impact Journals | en_GB |
dc.rights | This is a free access article. Available from Impact Journals via the DOI in this record. Licensed under a Creative Commons Attribution 3.0 License. https://creativecommons.org/licenses/by/3.0/ | en_GB |
dc.subject | PAR-1 | en_GB |
dc.subject | TGFβ | en_GB |
dc.subject | cancer | en_GB |
dc.subject | thrombin | en_GB |
dc.title | TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2016-10-21T11:55:03Z | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.journal | Oncotarget | en_GB |
dc.identifier.pmid | 27566553 | |