Research Papers:

Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer

Óscar Aguilera, José Manuel González-Sancho, Sandra Zazo, Raúl Rincón, Agustín F. Fernández, Olga Tapia, Francesc Canals, Beatriz Morte, Vincenzo Calvanese, José L. Orgaz, Núria Niell, Susana Aguilar, José M. Freije, Osvaldo Graña, David G. Pisano, Aurea Borrero, Javier Martínez-Useros, Benilde Jiménez, Mario F. Fraga, Jesús García-Foncillas, Carlos López-Otín, Miguel Lafarga, Federico Rojo and Alberto Muñoz _

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Oncotarget. 2015; 6:5903-5917. https://doi.org/10.18632/oncotarget.3464

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Óscar Aguilera1,2,*, José Manuel González-Sancho1,*, Sandra Zazo2, Raúl Rincón2, Agustín F. Fernández3, Olga Tapia4,11, Francesc Canals5, Beatriz Morte1,6, Vincenzo Calvanese3,13, José L. Orgaz1,12, Núria Niell1, Susana Aguilar7, José M. Freije8, Osvaldo Graña9, David G. Pisano9, Aurea Borrero2, Javier Martínez-Useros2, Benilde Jiménez1, Mario F. Fraga3,10, Jesús García-Foncillas2, Carlos López-Otín8, Miguel Lafarga4, Federico Rojo2 and Alberto Muñoz1

1 Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain

2 Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain

3 Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, Oviedo, Spain

4 Departamento de Anatomía y Biología Celular, Universidad de Cantabria-IFIMAV, Santander, Spain

5 Proteomics Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona, Spain

6 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

7 Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain

8 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain

9 Bioinformatics Unit and Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, Madrid, Spain

10 Department of Immunology and Oncology, Centro Nacional de Biotecnología (CSIC), Madrid, Spain

11 Present address: The Scripps Research Institute, La Jolla, CA, USA

12 Present address: Randall Division of Cell and Molecular Biophysics, King’s College London, United Kingdom

13 Present address: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, CA, USA

* These authors contributed equally to the work

Correspondence to:

Alberto Muñoz, email:

Federico Rojo, email:

Keywords: Colorectal cancer, Dickkopf-1, chemoresistance, ALDH1A1, biomarker

Received: October 29, 2014 Accepted: January 22, 2015 Published: February 28, 2015


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 cancer-related 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 and 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.

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