Genomics

Dataset Information

298

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. Analysis of DKK-1 location and associated roles in human colon cancer cells and crypts of small and large bowel.

ORGANISM(S): Homo sapiens  

SUBMITTER: Agustin F Fernandez   Javier Martínez-Useros  Carlos López-Otin  Jesús García-Foncillas  Jose M González-Sancho  Beatriz Morte  Jose L Orgaz  Nuria Niell  Oscar Aguilera  Francesc Canals  Benilde Jimenez  Alberto Muñoz  Jose M Freije  Olga Tapia  Aurea Borrero  Federico Rojo  David G Pisano  Osvaldo Graña  Miguel Lafarga  Calvanese Vincenzo  Sandra Zazo  Mario F Fraga  Susana Aguilar  Raúl Rincón 

PROVIDER: E-GEOD-31170 | ArrayExpress | 2015-05-13

SECONDARY ACCESSION(S): SRP007652GSE31170PRJNA144793

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications


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-r  ...[more]

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