DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth
| Autor: | Meritxell Gironella, Estela Núñez-Manchón, Miriam Cuatrecasas, Eva C. Vaquero, Xavier Bofill-De Ros, Maria L. Arbonés, Cristina Fillat, Jacopo Boni, Susana de la Luna, Jeroni Luna |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Generalitat de Catalunya, Instituto de Salud Carlos III, European Commission, European Cooperation in Science and Technology |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
C-Met endocrine system diseases DYRK1A Adenocarcinoma Protein Serine-Threonine Kinases Biology medicine.disease_cause Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Pancreatic cancer medicine Animals Humans Cell Proliferation Gene knockdown Cell growth Kinase Intracellular Signaling Peptides and Proteins Gastroenterology Membrane Proteins Protein-Tyrosine Kinases Proto-Oncogene Proteins c-met medicine.disease digestive system diseases Fibroblast Growth Factors Gene Expression Regulation Neoplastic Pancreatic Neoplasms 030104 developmental biology chemistry SPRY2 Cancer research 030211 gastroenterology & hepatology Carcinogenesis Carcinoma Pancreatic Ductal Signal Transduction |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1468-3288 0017-5749 |
| Popis: | [Background and aims]: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumour with a poor prognosis using current treatments. Targeted therapies may offer a new avenue for more effective strategies. Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase with contradictory roles in different tumours that is uncharacterised in PDAC. Here, we aimed to investigate the role of DYRK1A in pancreatic tumorigenesis. [Design]: We analysed DYRK1A expression in PDAC genetic mouse models and in patient samples. DYRK1A function was assessed with knockdown experiments in pancreatic tumour cell lines and in PDAC mouse models with genetic reduction of Dyrk1a dosage. Furthermore, we explored a mechanistic model for DYRK1A activity. [Results]: We showed that DYRK1A was highly expressed in PDAC, and that its protein level positively correlated with that of c-MET. Inhibition of DYRK1A reduced tumour progression by limiting tumour cell proliferation. DYRK1A stabilised the c-MET receptor through SPRY2, leading to prolonged activation of extracellular signal-regulated kinase signalling. [Conclusions]: These findings reveal that DYRK1A contributes to tumour growth in PDAC, at least through regulation of c-MET accumulation, suggesting that inhibition of DYRK1A could represent a novel therapeutic target for PDAC. This work was supported by grants from the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) (BIO2014-57716-C2-2-R, BIO2017-89754-C2-2R to CF and BFU2016-76141-P to SL), and receives partial support from the Generalitat de Catalunya (SGR14/248 to CF and SGR14/674 to SL). CIBER de Enfermedades Raras and de Enfermedades Hepáticas y Digestivas are initiatives of the Instituto de Salud Carlos III (ISCIII). The group of CF is partially financed by the ISCIII (IIS10/00014), co-financed by Fondo Europeo de Desarrollo Regional (FEDER), and acknowledges the support of the COST Action BM1204 EUPancreas. MG acknowledges grant PI17/01003 from ISCIII. |
| Databáze: | OpenAIRE |
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