title: TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells.
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.
authors: Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK.
authors: Natalia
authors: N
authors: Smoktunowicz
authors: Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK.
authors: Manuela
authors: M
authors: Platé
authors: Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK.
authors: Alejandro Ortiz
authors: AO
authors: Stern
authors: Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK.
authors: Vanessa
authors: V
authors: D'Antongiovanni
authors: Department of Chemistry, University College London, London, UK.
authors: Eifion
authors: E
authors: Robinson
authors: Department of Chemistry, University College London, London, UK.
authors: Vijay
authors: V
authors: Chudasama
authors: Department of Chemistry, University College London, London, UK.
authors: Stephen
authors: S
authors: Caddick
authors: Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK.
authors: Chris J
authors: CJ
authors: Scotton
authors: Novartis Institutes of Biomedical Research, Horsham, UK.
authors: Gabor
authors: G
authors: Jarai
authors: Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK.
authors: Rachel C
authors: RC
authors: Chambers
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000276:immunology*; D001777:Blood Coagulation; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism; D039641:Integrin beta Chains / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology*; D020935:MAP Kinase Signaling System; D011494:Protein Kinases / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D039482:Integrin alpha5; D039641:Integrin beta Chains; D044463:Receptor, PAR-1; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C072170:integrin beta6; D011494:Protein Kinases; C065999:Sp1 kinase; D013917:Thrombin
keywords: PAR-1; TGFβ; cancer; thrombin