International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China.
Clin Cancer Res. 2013 Apr 15;19(8):2014-24. doi: 10.1158/1078-0432.CCR-12-0349. Epub 2013 Mar 14.
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.
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.
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.
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.
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很好的证实。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。
纳入了两个独立的 200 例 ICC 患者队列。通过实时 PCR 和免疫组织化学检测评估 hedgehog 成分的表达。确定并验证了 hedgehog 蛋白的预后价值。使用环巴胺或靶向 Gli 的 siRNA 阻断 hedgehog 信号。通过 CCK8、细胞周期和 Annexin V 染色检测观察细胞增殖和凋亡。使用体内小鼠肿瘤模型评估 hedgehog 在 ICC 中的作用。
在 ICC 组织中，Gli1 核免疫强度与肝内转移有关，Gli2 的表达与肝内转移、静脉侵犯和国际抗癌联盟（UICC）pT 特征有关。在生存分析中，高 Gli1 或 Gli2 表达者的总生存（OS）预后不良，无病生存（DFS）较低表达者更短。多变量分析显示，Gli1 表达是 OS 的独立预后因素，这在另一个独立队列中得到了验证。此外，环巴胺或靶向 Gli1 的 siRNA 阻断 hedgehog 信号可导致 ICC 细胞凋亡和生长抑制。
本研究首次表明 hedgehog 通路的激活与 ICC 的进展和转移有关，这可能为该肿瘤提供预后和治疗价值。
