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Updated: Jun 21, 2026
In vitro Organoid Culture of Primary Mouse Colon Tumors
Published on: May 17, 2013
DICKKOPF-4 and -2 genes are upregulated in human colorectal cancer
Akira Matsui1, Tatsuya Yamaguchi, Shinya Maekawa
1First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, Japan.
Abstract:
To comprehensively screen for genetic events underlying colorectal cancer, we performed suppression subtraction hybridization analysis on an advanced colon cancer. Because Dickkopf-4, a member of the Dickkopf family acting as a Wnt-signaling modulator, was identified as one of the upregulated genes in this specimen, we investigated expression profiles of all the Dickkopf family members in 55 colorectal tumors (21 cancers and 34 adenomas). We also investigated mechanisms regulating the expression of Dickkopf-4 in these cancers in vitro and in vivo. Compared with normal adjacent mucosae, Dickkopf-4 (median 27.4, P < 0.01) and -2 (median 51.4, P < 0.01) were strongly expressed in colorectal cancers. The level of Dickkopf-4 was positively correlated with fibroblast growth factor-20 (r(s) = 0.61, P = 0.00017), a representative beta-catenin transcriptional target gene, and with the degree of nuclear accumulation of beta-catenin in colorectal tumors. Dickkopf-4 was induced by activated beta-catenin in vitro. Reciprocally, recombinant Dickkopf-4 significantly inhibited T-cell factor/lymphocyte enhancer factor reporter activity stimulated by recombinant Wnt3a in human embryonic kidney 293 cells. We conclude that Dickkopf-4 and -2 are significantly upregulated in most colorectal tumors, and that Dickkopf-4 upregulation reflects activation of the Wnt/canonical pathway.
Insights
Dickkopf-4 and Dickkopf-2 genes are significantly upregulated in colorectal tumors, indicating activation of the Wnt signaling pathway. This finding offers new insights into colorectal cancer development and potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Colorectal cancer (CRC) arises from complex genetic alterations.
- The Wnt signaling pathway plays a crucial role in CRC pathogenesis.
- Dickkopf family proteins are modulators of Wnt signaling.
Purpose of the Study:
- To screen for genetic events in colorectal cancer.
- To investigate the expression profiles of Dickkopf family members in colorectal tumors.
- To elucidate the regulatory mechanisms of Dickkopf-4 in CRC.
Main Methods:
- Suppression subtraction hybridization (SSH) for gene screening.
- Quantitative analysis of Dickkopf gene expression in 55 colorectal tumors and adjacent normal mucosa.
- In vitro and in vivo studies to assess Dickkopf-4 regulation by beta-catenin and its effect on Wnt signaling.
Main Results:
- Dickkopf-4 and Dickkopf-2 showed significant upregulation in colorectal cancers compared to normal mucosa.
- Dickkopf-4 expression positively correlated with fibroblast growth factor-20 and nuclear beta-catenin accumulation.
- Activated beta-catenin induced Dickkopf-4 expression in vitro, and Dickkopf-4 inhibited Wnt3a-stimulated TCF/LEF reporter activity.
Conclusions:
- Dickkopf-4 and Dickkopf-2 are frequently upregulated in colorectal tumors.
- Upregulation of Dickkopf-4 is associated with activated Wnt/canonical pathway signaling in CRC.
- These findings highlight the role of Dickkopf family members in colorectal carcinogenesis.
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