TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells
| Autor: | Vanessa D’Antongiovanni, Manuela Platé, Rachel C. Chambers, Eifion Robinson, Alejandro Ortiz Stern, Vijay Chudasama, Chris J. Scotton, Gabor Jarai, Stephen Caddick, Natalia Smoktunowicz |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Integrin beta Chains Lung Neoplasms Cancer PAR-1 TGFβ Thrombin A549 Cells Adenocarcinoma Blood Coagulation Cell Movement Gene Expression Regulation Neoplastic Humans Integrin alpha5 MAP Kinase Signaling System Protein Kinases Receptor PAR-1 Smad3 Protein Transforming Growth Factor beta Up-Regulation Oncology medicine.medical_treatment 03 medical and health sciences Downregulation and upregulation Thrombin receptor medicine cancer A549 cell Neoplastic biology business.industry Transforming growth factor beta medicine.disease 3. Good health 030104 developmental biology Cytokine Gene Expression Regulation Immunology biology.protein Cancer research business medicine.drug Receptor Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Natalia Smoktunowicz 1 , Manuela Plate 1 , Alejandro Ortiz Stern 1 , Vanessa D’Antongiovanni 1 , Eifion Robinson 2 , Vijay Chudasama 2 , Stephen Caddick 2 , Chris J. Scotton 1 , Gabor Jarai 3 , Rachel C. Chambers 1 1 Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK 2 Department of Chemistry, University College London, London, UK 3 Novartis Institutes of Biomedical Research, Horsham, UK Correspondence to: Rachel C. Chambers, email: r.chambers@ucl.ac.uk Keywords: PAR-1, TGFβ, thrombin, cancer Received: February 12, 2016 Accepted: August 06, 2016 Published: August 22, 2016 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. |
| Databáze: | OpenAIRE |
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