Immunohistochemical and mutational analyses of Wnt signaling components and target genes in intrahepatic cholangiocarcinomas.
Immunohistochemical and mutational analyses of Wnt signaling components and target genes in intrahepatic cholangiocarcinomas.
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DOI：
10.3892/ijo.27.4.973
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发表时间：
2005-10
影响因子：
5.2
通讯作者：
N. Tokumoto;S. Ikeda;Y. Ishizaki;T. Kurihara;S. Ozaki;M. Iseki;Y. Shimizu;T. Itamoto;K. Arihiro;M. Okajima;T. Asahara
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文献类型：
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作者：
N. Tokumoto;S. Ikeda;Y. Ishizaki;T. Kurihara;S. Ozaki;M. Iseki;Y. Shimizu;T. Itamoto;K. Arihiro;M. Okajima;T. Asahara
肝内胆管细胞癌(ICC)的致癌机制尚不清楚，但已有多个癌基因和抑癌基因发生改变的报道。在本研究中，我们通过分析24个手术切除的ICC样本，重点研究了Wnt信号成分和靶基因的变化。免疫组织化学分析显示，58.3%的标本胞浆和/或胞核呈阳性染色，提示这些标本中存在Wnt信号通路的改变。在测序分析中，在24例ICC样本中，分别有8.3%、12.5%和41.7%的ICC组织中发现了β-连环蛋白、腺瘤性息肉病和Axin-1基因的突变，但这些突变基因的功能意义存在争议。此外，Wnt信号通路下游靶基因Cyclin D1、c-myc和尿型纤溶酶原激活物受体在24例ICC中分别有41.7%、41.7%和58.3%过表达。细胞周期蛋白D_1的过度表达与β-连环蛋白的过度表达呈正相关。根据这些结果，我们推测Wnt信号通路通过其靶基因，特别是细胞周期蛋白D1的过表达，在肝细胞癌的发生发展中起重要作用。
The mechanisms of carcinogenesis in intrahepatic cholangiocarcinoma (ICC) are not well characterized although alterations in several oncogenes and onco-suppressor genes have been reported to occur in ICC. In the present study, we focused on alterations in the Wnt signaling components and target genes by analyzing 24 surgically resected samples of ICC. Immunohistochemical analysis of beta-catenin showed positive staining in cytoplasm and/or nucleus in 58.3% of the samples, indicating the presence of alterations in the Wnt signaling pathway in these samples. In sequencing analyses, mutations in the beta-catenin, adenomatous polyposis coli and Axin 1 genes were observed in 8.3, 12.5 and 41.7%, respectively, of the 24 ICC samples; however, the functional significance of these mutated genes is controversial. Furthermore, cyclin D1, c-myc and urinary-type plasminogen activator receptor, which are the downstream target genes in the Wnt signaling pathway, were overexpressed in 41.7, 41.7 and 58.3%, respectively, of the 24 ICC samples. The overexpression of cyclin D1 was statistically correlated with that of beta-catenin. Based on these results, we speculated that the Wnt signaling pathway plays an important role in carcinogenesis in ICC through overexpression of its target genes, particularly cyclin D1.