Characterizing the activation of the Wnt signaling pathway in hilar cholangiocarcinoma using a tissue microarray approach.
Characterizing the activation of the Wnt signaling pathway in hilar cholangiocarcinoma using a tissue microarray approach.
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DOI：
10.4081/ejh.2016.2536
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发表时间：
2016-02-09
期刊：
影响因子：
--
通讯作者：
Zhang K
中科院分区：
文献类型：
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作者：
Chen W;Liang J;Huang L;Cai J;Lei Y;Lai J;Liang L;Zhang K
肝门部胆管癌（HCCA）是一种难以活检的浸润性肝脏恶性肿瘤，因此，需要新的HCCA预后标志物。在此，比较了HCCA、肝内胆管癌（IHCC）和先天性胆总管囊肿（CCC）患者的经典Wnt激活水平，以了解Wnt信号传导在HCCA中的作用。来自HCCA（n=129）、IHCC（n=31）和CCC（n=45）患者的病理标本用于构建组织微阵列。免疫组化检测Wnt 2、Wnt 3、β-catenin、TCF 4、c-Myc和细胞周期蛋白D1。平行相关分析用于分析HCCA、IHCC和CCC组之间蛋白水平的差异。单变量和多变量分析用于确定HCCA组成功切除和预后的独立预测因素。HCCA中Wnt 2、β-catenin、TCF 4、c-Myc和cyclin D1的蛋白水平显著高于IHHC或CCC。HCCA组织中Wnt信号传导激活（Wnt 2+、Wnt 3+、核β-catenin+、核TCF 4+）显著高于CCC组织。单变量分析表明，细胞周期蛋白D1的表达以及Wnt信号激活和部分Wnt激活（Wnt 2+或Wnt 3+和核β-连环蛋白+或核TCF 4+）预测成功切除，但只有细胞周期蛋白D1表达在多变量分析中仍然显着。只有部分Wnt激活是生存时间的独立预测因子。经典Wnt信号通路中的蛋白在HCCA中以较高水平存在，并且与肿瘤的易发性和患者预后相关。这些结果表明，Wnt通路分析可能是一个有用的标志物在HCCA的临床结果。
Hilar cholangiocarcinoma (HCCA) is an invasive hepatic malignancy that is difficult to biopsy; therefore, novel markers of HCCA prognosis are needed. Here, the level of canonical Wnt activation in patients with HCCA, intrahepatic cholangiocarcinoma (IHCC), and congenital choledochal cysts (CCC) was compared to understand the role of Wnt signaling in HCCA. Pathology specimens from HCCA (n=129), IHCC (n=31), and CCC (n=45) patients were used to construct tissue microarrays. Wnt2, Wnt3, β-catenin, TCF4, c-Myc, and cyclin D1 were detected by immunohistochemistry. Parallel correlation analysis was used to analyze differences in protein levels between the HCCA, IHCC, and CCC groups. Univariate and multivariate analyses were used to determine independent predictors of successful resection and prognosis in the HCCA group. The protein levels of Wnt2, β-catenin, TCF4, c-Myc, and cyclin D1 were significantly higher in HCCA compared to IHHC or CCC. Wnt signaling activation (Wnt2+, Wnt3+, nuclear β-catenin+, nuclear TCF4+) was significantly greater in HCCA tissues than CCC tissues. Univariable analyses indicated that expression of cyclin D1 as well as Wnt signaling activation, and partial Wnt activation (Wnt2+ or Wnt3+ and nuclear β-catenin+ or nuclear TCF4+) predicted successful resection, but only cyclin D1 expression remained significant in multivariable analyses. Only partial Wnt activation was an independent predictor of survival time. Proteins in the canonical Wnt signaling pathway were present at higher levels in HCCA and correlated with tumor resecility and patient prognosis. These results suggest that Wnt pathway analysis may be a useful marker for clinical outcome in HCCA.