title: Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.
abstract: 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.
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors: Óscar
authors: Ó
authors: Aguilera
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.
authors: José Manuel
authors: JM
authors: González-Sancho
authors: Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors: Sandra
authors: S
authors: Zazo
authors: Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors: Raúl
authors: R
authors: Rincón
authors: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, Oviedo, Spain.
authors: Agustín F
authors: AF
authors: Fernández
authors: Departamento de Anatomía y Biología Celular, Universidad de Cantabria-IFIMAV, Santander, Spain.|Present address: The Scripps Research Institute, La Jolla, CA, USA.
authors: Olga
authors: O
authors: Tapia
authors: Proteomics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.
authors: Francesc
authors: F
authors: Canals
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors: Beatriz
authors: B
authors: Morte
authors: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, Oviedo, Spain.|Present address: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, CA, USA.
authors: Vincenzo
authors: V
authors: Calvanese
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.|Present address: Randall Division of Cell and Molecular Biophysics, King's College London, United Kingdom.
authors: José L
authors: JL
authors: Orgaz
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.
authors: Núria
authors: N
authors: Niell
authors: Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Susana
authors: S
authors: Aguilar
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors: José M
authors: JM
authors: Freije
authors: Bioinformatics Unit and Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors: Osvaldo
authors: O
authors: Graña
authors: Bioinformatics Unit and Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors: David G
authors: DG
authors: Pisano
authors: Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors: Aurea
authors: A
authors: Borrero
authors: Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors: Javier
authors: J
authors: Martínez-Useros
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.
authors: Benilde
authors: B
authors: Jiménez
authors: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, Oviedo, Spain.|Department of Immunology and Oncology, Centro Nacional de Biotecnología (CSIC), Madrid, Spain.
authors: Mario F
authors: MF
authors: Fraga
authors: Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors: Jesús
authors: J
authors: García-Foncillas
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors: Carlos
authors: C
authors: López-Otín
authors: Departamento de Anatomía y Biología Celular, Universidad de Cantabria-IFIMAV, Santander, Spain.
authors: Miguel
authors: M
authors: Lafarga
authors: Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors: Federico
authors: F
authors: Rojo
authors: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.
authors: Alberto
authors: A
authors: Muñoz
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D011379:Prognosis; D050697:Retinal Dehydrogenase; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C489722:REPS2 protein, human; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
keywords: ALDH1A1; Dickkopf-1; biomarker; chemoresistance; colorectal cancer