The Prognostic Significance and Therapeutic Potential of Hedgehog Signaling in Intrahepatic Cholangiocellular Carcinoma
The Prognostic Significance and Therapeutic Potential of Hedgehog Signaling in Intrahepatic Cholangiocellular Carcinoma
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Hedgehog 信号转导在肝内胆管细胞癌中的预后意义和治疗潜力
DOI：
10.1158/1078-0432.ccr-12-0349
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发表时间：
2013-04-15
影响因子：
11.5
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
--
作者：
Tang, Liang;Tan, Ye-Xiong;Wang, Hong-Yang
目的：hedgehog 信号通路与肝内胆管细胞癌 (ICC) 的进展、预后和治疗的相关性尚未得到充分记录。本研究旨在探讨hedgehog成分在ICC中的表达、预后意义和治疗价值。实验设计：纳入了由 200 名 ICC 患者组成的两个独立队列。通过实时PCR和免疫组织化学检测，评估hedgehog成分的表达。刺猬蛋白的预后价值得到了鉴定和验证。环巴明或 siRNA 靶向 Gli 用于阻断刺猬信号传导。通过 CCK8、细胞周期和膜联蛋白 V 染色分析观察细胞增殖和凋亡。使用体内小鼠肿瘤模型来评估hedgehog在ICC中的作用。结果：在ICC组织中，Gli1的核免疫强度与肝内转移相关，Gli2的表达与肝内转移、静脉侵犯和国际抗癌联盟（UICC）pT特征相关。在生存分析中，Gli1或Gli2高表达者比低表达者具有不利的总生存（OS）预后和更短的无病生存（DFS）。在多变量分析中，发现 Gli1 表达是 OS 的独立预后因素，并得到了另一个独立队列的验证。此外，通过环杷明或靶向Gli1的siRNA阻断hedgehog信号传导会导致ICC细胞凋亡和生长抑制。结论：本研究首次表明hedgehog通路的激活与ICC的进展和转移相关，这可能为该肿瘤的预后和治疗提供价值。临床癌症研究； 19(8)； 2014–24。 ©2013 AACR。
Purpose: The correlation of the hedgehog signaling pathway with the progression, prognosis, and therapeutics of intrahepatic cholangiocellular carcinoma (ICC) has not been well documented. The study aimed to investigate the expression, prognostic significance, and therapeutic value of hedgehog components in ICC. Experimental Design: Two independent cohorts of 200 patients with ICC were enrolled. By real-time PCR and immunohistochemistry assay, hedgehog components expression was evaluated. The prognostic values of hedgehog proteins were identified and verified. Cyclopamine or siRNA-targeting Gli was used to block the hedgehog signaling. Cell proliferation and apoptosis were observed by CCK8, cell cycle, and annexin V staining assays. In vivo murine tumor model was used to evaluate the role of hedgehog in ICC. Results: In ICC tissues, the Gli1 nuclear immune-intensity was associated with intrahepatic metastasis and the expression of Gli2 was associated with intrahepatic metastasis, venous invasion, and Unio Internationale Contra Cancrum (UICC) pT characteristics. In survival analysis, high Gli1 or Gli2 expressers had an unfavorable overall survival (OS) prognosis and a shorter disease-free survival (DFS) than those with low expression. In multivariate analysis, Gli1 expression was found to be an independent prognostic factor of OS, which was validated by another independent cohort. Furthermore, blocking the hedgehog signaling by cyclopamine or siRNA-targeting Gli1 resulted in apoptosis and growth inhibition in ICC cells. Conclusions: This study shows, for the first time, activation of hedgehog pathway associated with the progression and metastasis in ICC, which may provide prognostic and therapeutic values for this tumor. Clin Cancer Res; 19(8); 2014–24. ©2013 AACR.