The Wnt antagonist DICKKOPF-1 gene is a downstream target of β-catenin/TCF and is downregulated in human colon cancer

Universidad Autónoma de Madrid, Madrid, Madrid, Spain
Oncogene (Impact Factor: 8.46). 03/2005; 24(6):1098-103. DOI: 10.1038/sj.onc.1208303
Source: PubMed


Wnt glycoproteins regulate homeostasis and development by binding to membrane Frizzled-LRP5/6 receptor complexes. Wnt signaling includes a canonical pathway involving cytosolic beta-catenin stabilization, nuclear translocation and gene regulation, acting as a co-activator of T-cell factor (TCF) proteins, and noncanonical pathways that activate Rho, Rac, JNK and PKC, or modulate Ca(2+) levels. DICKKOPF-1 (DKK-1) encodes a secreted Wnt antagonist that binds to LRP5/6 and induces its endocytosis, leading to inhibition of the canonical pathway. We show that activation of canonical signaling by Wnt1 or ectopic expression of active beta-catenin, TCF4 or LRP6 mutants induces transcription of the human DKK-1 gene. Multiple beta-catenin/TCF4 sites in the DKK-1 gene promoter contribute to this activation. In contrast, Wnt5a, which signals through noncanonical pathways, does not activate DKK-1. Northern and Western blot studies show that activation of the Wnt/beta-catenin pathway by treatment with lithium or Wnt3a-conditioned medium, or by stable expression of either Wnt1 or beta-catenin, increases DKK-1 RNA and protein, thus initiating a negative feedback loop. However, we found that DKK-1 expression decreases in human colon tumors, which suggests that DKK-1 acts as a tumor suppressor gene in this neoplasia. Our data indicate that the Wnt/beta-catenin pathway is downregulated by the induction of DKK-1 expression, a mechanism that is lost in colon cancer.

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    • "Wnt/β-catenin signaling is a key regulator of both normal development and tumorigenesis, and its deregulation is involved in various human cancers, such as colon cancer, breast cancer, prostate cancer and glioma [1] [2] [3] [4]. The canonical Wnt pathway includes Wnt protein ligands, the Frizzled and LRP membrane receptors, the key transcriptional factor β-catenin, the GSK-3/APC/Axin degradation complex, LEF/TCF coactivators and downstream targets such as cyclinD1 [5]. "
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    ABSTRACT: Inhibitor of β-catenin and T-cell factor (ICAT) is a key component of Wnt/β-catenin signaling. ICAT blocks the formation of the β-catenin/TCF complex and has been demonstrated to be involved in embryonic development and carcinogenesis. As an inhibitor of canonical Wnt signaling, ICAT was presumed to be a tumor-suppressor gene. However, the ICAT functions in human glioma remain unknown. In this study, we evaluated the expression of ICAT in 305 human glioma tissues and found that negative ICAT expression correlated with higher grade glioma and poor survival in patients with glioma. Then we transfected glioma cells with ICAT plasmid. Western blotting showed an increased ICAT protein expression level in glioma cells. MTT assay, flow cytometry and cell invasion assay were used to detect cell proliferation, cell cycle distribution, apoptosis and invasion. Our studies confirmed that ICAT inhibits glioma cell proliferation and invasion, and it induces cell apoptosis and cell cycle progression arrest. Besides, ICAT slowed down tumor growth in a glioblastoma xenograft model. Therefore, our study demonstrates that ICAT may serve as a tumor-suppressor in human glioma suggesting a promising direction for targeting therapy in glioma. Copyright © 2014. Published by Elsevier Ireland Ltd.
    Full-text · Article · Nov 2014 · Cancer Letters
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    • "The expression and roles of DKK-1 are different in various cancers, current studies have reported that overexpression of DKK-1 is found in many malignant tumors, including lung cancer, esophageal carcinomas, cervical cancer, and hepatocellular carcinoma (HCC), indicating a potential oncogenic function of DKK-1 [10-13]. However, paradoxically, the expression of DKK-1 was down-regulated significantly in human colon cancer, gastric cancer and melanoma [14-16], suggesting that the function of DKK-1 may be different in different types of cancers. In spite of these studies, there little has been reported on the significance of DKK-1 expression in breast cancer progression and prognosis. "
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    ABSTRACT: Background The different expression level of Dickkopf-1 (DKK-1) in different cancers shows that the function of DKK-1 depends on the histological type of the cancer cells and the tissue microenvironment. To our knowledge, the serum expression level of DKK-1 in breast cancer is little known.Methods Blood samples from 125 consecutive patients diagnosed with breast cancer and 53 control subjects from March 2008 to August 2013 were investigated. Serum DKK-1 expression levels were measured by enzyme-linked immunosorbent assay (ELISA). The overall survival (OS) and relapse-free survival (RFS) analyzed by log-rank test, and survival curves were plotted according to Kaplan¿Meier.ResultsThe mean serum level of DKK-1 in patients with breast cancer was 4.99¿±¿1.50 ng/mL, and was significantly higher than that in healthy individuals (1.88¿±¿0.81 ng/mL, P¿<¿0.001). DKK-1 level correlated significantly with TNM stage (P¿=¿0.009), tumor grade (P¿=¿0.02), lymph node metastasis (P¿=¿0.001), and expression of HER2 (P¿=¿0.002). The DKK-1 expression level was classified as high or low in relation to the median value, and patients with breast cancer (n¿=¿125) were divided into a high expression group (n¿=¿63) and a low expression group (n¿=¿62). The Kaplan-Meier method for survival analysis showed that the patients with a high serum DKK-1 level had a poorer OS (48.7% vs. 81.3%, p¿=¿0.01) and RFS (24.3% vs. 71.6%, p¿=¿0.003) than those with a low expression level. The multivariate Cox regression analysis indicated that serum DKK-1 level was independent prognostic factors for OS and RFS.Conclusions Serum DKK-1 level can be used as a noninvasive biomarker for the prognosis of breast cancer.Virtual SlidesThe virtual slide(s) for this article can be found here:
    Full-text · Article · Aug 2014 · Diagnostic Pathology
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    • "DKK1 also exhibits binding sites for HOXA10.[48] Because DKK1 can inhibit the WNT/β-catenin pathway[49], [50] whereas its own expression is induced by the β-catenin/TCF complex[39], DKK1 imposes a negative force-feedback loop on itself[51] and can suppress expression of β-catenin target molecules such as CCND1. In breast cancer and colon cancer cells it has been found that inhibition of β-catenin might enhance invasive potential via upregulation of uPA/uPAR at mRNA and protein level[52]. "
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    ABSTRACT: Lymph node metastasis indicates poor prognosis in esophageal cancer. To understand the underlying mechanisms, most studies so far focused on investigating the tumors themselves and/or invaded lymph nodes. However they neglected the potential events within the metastatic niche, which precede invasion. Here we report the first description of these regulations in patients on transcription level. We determined transcriptomic profiles of still metastasis-free regional lymph nodes for two patient groups: patients classified as pN1 (n = 9, metastatic nodes exist) or pN0 (n = 5, no metastatic nodes exist). All investigated lymph nodes, also those from pN1 patients, were still metastasis-free. The results show that regional lymph nodes of pN1 patients differ decisively from those of pN0 patients - even before metastasis has taken place. In the pN0 group distinct immune response patterns were observed. In contrast, lymph nodes of the pN1 group exhibited a clear profile of reduced immune response and reduced proliferation, but increased apoptosis, enhanced hypoplasia and morphological conversion processes. DKK1 was the most significant gene associated with the molecular mechanisms taking place in lymph nodes of patients suffering from metastasis (pN1). We assume that the two molecular profiles observed constitute different stages of a progressive disease. Finally we suggest that DKK1 might play an important role within the mechanisms leading to lymph node metastasis.
    Full-text · Article · Jul 2014 · PLoS ONE
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