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.
Highlights
Colorectal cancer (CRC) is an important contributor to cancer mortality and morbidity [1]
Nuclear DKK-1 expression was detected in enteroendocrine cells at the bottom of the crypts, as revealed by co-expression of chromogranin A (Fig. 1B)
We studied the expression of DKK-1 in human colon carcinoma cells both in vitro and in a large cohort of metastatic CRC patients
Summary
Colorectal cancer (CRC) is an important contributor to cancer mortality and morbidity [1]. Despite advances in therapy for CRC patients, approximately 20-45% of those who undergo curative resection subsequently develop tumor recurrence or distant metastasis [2]. Abnormal activation of the Wnt/β-catenin pathway due to mutation of APC, CTNNB1/β-catenin or AXIN genes is the initial event and a driving force of colorectal tumorigenesis [4]. DKK-1 modulates proliferation and survival of cancer cells in which the Wnt/β-catenin pathway is constitutively activated by mutations in genes encoding intracellular pathway components, or independently of β-catenin transcriptional activity [7, 8]. Available data indicate the existence of uncharacterized actions of DKK1 that are independent of the inhibition of Wnt signaling at plasma membrane
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