Research Papers:
Under-expression of CK2β subunit in ccRCC represents a complementary biomarker of p-STAT3 Ser727 that correlates with patient survival
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Abstract
Jordi Vilardell1,*, Estefania Alcaraz1,*, Eduard Sarró2, Enric Trilla3, Thaïs Cuadros2, Inés de Torres4, Maria Plana1,5, Santiago Ramón y Cajal4,6, Lorenzo A. Pinna7, Maria Ruzzene7, Juan Morote3, Anna Meseguer2,8,9,10,# and Emilio Itarte1,5,#
1Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
2Fisiopatología Renal, CIBBIM, VHIR, Barcelona, Spain
3Servicio de Urología, Hospital Vall d’Hebrón, Barcelona, Spain
4Servicio de Anatomía Patológica, Hospital Vall d’Hebrón, Barcelona, Spain
5Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
6Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Barcelona, Spain
7Department of Biomedical Sciences and CNR Institute of Neuroscience, University of Padova, Padova, Italy
8Departament de Bioquimica i Biologia Molecular, Unitat de Bioquímica de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
9Instituto Reina Sofía de Investigación Nefrológica, Fundación Renal Íñigo Álvarez de Toledo, Madrid, Spain
10Red de Investigación Renal (REDINREN), Barcelona, Spain
*These authors contributed equally to this work
#Co-seniorship
Correspondence to:
Anna Meseguer, email: [email protected]
Emilio Itarte, email: [email protected]
Keywords: protein kinase CK2; clear cell renal cell carcinoma (ccRCC); epithelial-to-mesenchymal transition (EMT); STAT3; patient outcome
Received: March 22, 2017 Accepted: December 13, 2017 Published: December 19, 2017
ABSTRACT
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of renal cancer. STAT3 pathway is altered in these tumors and p-STAT3 Ser727 is an independent prognostic factor for ccRCC. Protein kinase CK2 is altered in different types of tumors and overexpression of CK2α is considered predictive of bad prognosis and metastatic risk. CK2 subunits analyses in ccRCC samples showed increased CK2α/α’ nuclear content in all cases, but decreased cytosolic CK2β (CK2βcyt) levels in the more advanced tumors. Stable downregulation of CK2β in renal proximal tubular (HK-2) and clear cell adenocarcinoma (786-O) cells triggered changes in E-cadherin, vimentin and Snail1 protein levels indicative of epithelial-to-mesenchymal transition (EMT), and increased HIF-α. Moreover, CK2β was required in order to observe STAT3 Ser727 phosphorylation in HK-2 but not in 786-O cells.
We also observed that CK2β improved the prognostic value of p-STAT3 Ser727, as CK2βcyt>41 (median value) discriminates patients free of disease for a period of 10 years upon surgery, from those with CK2βcyt<41, when p-STAT3 Ser727levels are low.
We conclude that CK2β down-regulation might represent a mechanism to support EMT and angiogenesis and that CK2βcyt levels are instrumental to refine prognosis of ccRCC patients with low p-STAT3 Ser727 levels.
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