DICKKOPF-4 is induced by TCF/β-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1α, 25-dihydroxyvitamin D3
DICKKOPF-4 is induced by TCF/β-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1α, 25-dihydroxyvitamin D3
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DOI：
10.1038/onc.2008.88
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发表时间：
2008-07-24
期刊：
影响因子：
8
通讯作者：
Gonzalez-Sancho, J. M.
中科院分区：
文献类型：
--
作者：
Pendas-Franco, N.;Garcia, J. M.;Gonzalez-Sancho, J. M.
Wnt/β-连环蛋白信号通路的异常激活是结肠癌的一个标志。我们发现，在人结肠癌细胞中，Wnt 拮抗剂 DICKKOPF-4 (DKK-4) 基因受到 1 α, 25-二羟基维生素 D-3 (1,25(OH)(2)D-3) 的抑制。该效应与 DKK-4 启动子的抑制相关。染色质免疫沉淀分析显示，1,25(OH)(2)D-3 诱导维生素 D 受体 (VDR) 和 SMRT 辅阻遏物与 DKK-4 转录起始位点附近的区域早期且短暂地结合。此外，我们证明 DKK-4 基因是 TCF/β-连环蛋白的新下游靶标。值得注意的是，在一系列 29 份人类正常 (N) 结肠活检中未检测到 DKK-4 信使 RNA (mRNA) 的表达，但在所有匹配的肿瘤 (T) 组织中表达均上调。 Ts中DKK-4和VDR RNA的表达之间存在负相关。异位 DKK-4 表达增加了结肠癌细胞的迁移和侵袭特性，表达 DKK-4 的细胞的条件培养基 (CM) 增强了人原代微血管内皮细胞迁移和形成毛细血管样小管的能力。总之，DKK-4 在结肠癌中表达上调，并且与肿瘤细胞获得恶性特性有关。 DKK-4 下调是 1,25(OH)(2)D-3 的一种新作用，可能有助于其抗癌作用。
Aberrant activation of the Wnt/beta-catenin signaling pathway is a hallmark of colon cancer. We show that the Wnt antagonist DICKKOPF-4 (DKK-4) gene is repressed by 1 alpha, 25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) in human colon cancer cells. This effect correlated with the inhibition of the DKK-4 promoter. Chromatin immunoprecipitation assays revealed that 1,25(OH)(2)D-3 induces early and transient binding of the vitamin D receptor (VDR) and the SMRT corepressor to the region adjacent to the transcription start site of DKK-4. Additionally, we demonstrate that the DKK-4 gene is a new downstream target of TCF/beta-catenin. Remarkably, expression of DKK-4 messenger RNA (mRNA) was not detected in a series of 29 human normal (N) colon biopsies but expression was upregulated in all the matched tumour (T) tissues. An inverse correlation existed between the expression of DKK-4 and VDR RNA in the Ts. Ectopic DKK-4 expression increased the migration and invasion properties of colon cancer cells and conditioned media (CM) from DKK-4-expressing cells enhanced the capacity to migrate and form capillary-like tubules of human primary microvascular endothelial cells. In conclusion, DKK-4 is upregulated in colon cancer and is associated with the acquisition of malignant properties by neoplastic cells. DKK-4 downregulation is a novel effect of 1,25(OH)(2)D-3 that may contribute to its anticancer action.