DICKKOPF-4 and -2 genes are upregulated in human colorectal cancer
DICKKOPF-4 and -2 genes are upregulated in human colorectal cancer
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DOI：
10.1111/j.1349-7006.2009.01272.x
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发表时间：
2009-10-01
期刊：
影响因子：
5.7
通讯作者：
Enomoto, Nobuyuki
中科院分区：
文献类型：
--
作者：
Matsui, Akira;Yamaguchi, Tatsuya;Enomoto, Nobuyuki
为了全面筛查结直肠癌的遗传事件，我们对晚期结肠癌进行了抑制消减杂交分析。由于 Dickkopf 家族的成员 Dickkopf-4 作为 Wnt 信号调节剂，被确定为该样本中上调的基因之一，因此我们研究了 55 个结直肠肿瘤（21 个癌症和 34 个腺瘤）中所有 Dickkopf 家族成员的表达谱。我们还在体外和体内研究了这些癌症中 Dickkopf-4 表达的调节机制。与正常邻近粘膜相比，Dickkopf-4（中位数27.4，P < 0.01）和-2（中位数51.4，P < 0.01）在结直肠癌中强烈表达。 Dickkopf-4的水平与代表性β-catenin转录靶基因成纤维细胞生长因子-20（r(s) = 0.61，P = 0.00017）以及结直肠肿瘤中β-catenin核积聚程度呈正相关。 Dickkopf-4 在体外由活化的 β-catenin 诱导。相反，重组 Dickkopf-4 显着抑制人胚肾 293 细胞中重组 Wnt3a 刺激的 T 细胞因子/淋巴细胞增强因子报告活性。我们得出结论，Dickkopf-4 和 -2 在大多数结直肠肿瘤中显着上调，并且 Dickkopf-4 上调反映了 Wnt/规范途径的激活。 （《癌症科学》2009 年；100：1923-1930）。
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. (Cancer Sci 2009; 100: 1923-1930).