Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer
| Autor: | Núria Niell, Vincenzo Calvanese, Federico Rojo, José M. Freije, José Manuel González-Sancho, Agustín F. Fernández, Sandra Zazo, David G. Pisano, Jesús García-Foncillas, Francesc Canals, Jose L. Orgaz, Alberto Muñoz, Mario F. Fraga, Oscar Aguilera, Miguel Lafarga, Javier Martinez-Useros, Raúl Rincón, Olga Tapia, Susana Aguilar, Aurea Borrero, Beatriz Morte, Osvaldo Graña, Benilde Jiménez, Carlos López-Otín |
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| Přispěvatelé: | Instituto de Salud Carlos III, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), European Commission, Universidad de Cantabria, UAM. Departamento de Bioquímica, UAM. Departamento de Medicina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Gerontology Colorectal cancer Medicina Colon mucosa Sporadic colorectal cancer Aldehyde Dehydrogenase 1 Family Dickkopf-1 Intestinal mucosa Cell Line Tumor Biomarkers Tumor Overall survival Humans Medicine Intestinal Mucosa ALDH1A1 Predictive biomarker Cell Nucleus business.industry Calcium-Binding Proteins Intracellular Signaling Peptides and Proteins Retinal Dehydrogenase Biomarker Aldehyde Dehydrogenase Prognosis University hospital medicine.disease Biología y Biomedicina / Biología Gene Expression Regulation Neoplastic Oncology Drug Resistance Neoplasm Intercellular Signaling Peptides and Proteins Female Colorectal Neoplasms business Humanities Chemoresistance Signal Transduction Research Paper |
| Zdroj: | Scopus-Elsevier Scopus RUO. Repositorio Institucional de la Universidad de Oviedo instname ResearcherID Oncotarget. 2015 Mar 20;6(8):5903-17 UCrea Repositorio Abierto de la Universidad de Cantabria Universidad de Cantabria (UC) Biblos-e Archivo. Repositorio Institucional de la UAM Europe PubMed Central Digital.CSIC. Repositorio Institucional del CSIC Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | This work is licensed under a Creative Commons Attribution 3.0 License.-- et al. Sporadic colorectal cancer (CRC) insurgence and progression depend on the activation of Wnt/β-catenin signaling. Dickkopf (DKK)-1 is an extracellular inhibitor of Wnt/β-catenin signaling that also has undefined β-catenin-independent actions. Here we report for the first time that a proportion of DKK-1 locates within the nucleus of healthy small intestine and colon mucosa, and of CRC cells at specific chromatin sites of active transcription. Moreover, we show that DKK-1 regulates several cancerrelated genes including the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) and Ral-binding protein 1-associated Eps domain-containing 2 (REPS2), which are involved in detoxification of chemotherapeutic agents. Nuclear DKK-1 expression is lost along CRC progression; however, it remains high in a subset (15%) of CRC patients (n = 699) and associates with decreased progression-free survival (PFS) after chemotherapy administration and overall survival (OS) [adjusted HR, 1.65; 95% confidence interval (CI), 1.23-2.21; P = 0.002)]. Overexpression of ALDH1A1 antiand REPS2 associates with nuclear DKK-1 expression in tumors and correlates with decreased OS (P = 0.001 and 0.014) and PFS. In summary, our findings demonstrate a novel location of DKK-1 within the cell nucleus and support a role of nuclear DKK-1 as a predictive biomarker of chemoresistance in colorectal cancer. This work was supported by grants from the Ministerio de Economía y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2013-43468-R, A.M.; BFU2010-19659, J.M.G-S.; SAF2010-19256, B.J.; SAF2011-23089, C.L-O.), Comunidad de Madrid (S2010/BMD-2344 Colomics2, A.M., F.R. and J.M.G-S.) and FEDER-Instituto de Salud Carlos III (RD12/0036/0021, A.M.; RD12/0036/0051, PT13/0010/0012 and PI12/01552, F.R.; ProteoRed Networked Proteomics Platform, F.C.). |
| Databáze: | OpenAIRE |
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