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Title

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

AuthorsAguilera, Óscar ; González-Sancho, José Manuel ; Zazo, Sandra; Fernández, Agustín F.; Morte, Beatriz ; Calvanese, Vincenzo; Orgaz, Jose L.; Niell, Núria ; Freije, José M. P.; Pisano, David G.; Jiménez, Benilde ; Fraga, Mario F.; López-Otín, Carlos; Lafarga, Miguel; Rojo, Federico; Muñoz Terol, Alberto
Issue Date2015
PublisherImpact Journals
CitationOncotarget 6(8): 5903-5917 (2015)
AbstractSporadic 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.
DescriptionThis work is licensed under a Creative Commons Attribution 3.0 License.-- et al.
Publisher version (URL)http://dx.doi.org/10.18632/oncotarget.3464
URIhttp://hdl.handle.net/10261/123010
DOI10.18632/oncotarget.3464
Identifiersdoi: 10.18632/oncotarget.3464
e-issn: 1949-2553
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