Kang Qiang, Cai Jia-Bin, Dong Rui-Zhao, Liu Li-Xin, Zhang Chi, Zhang Peng-Fei, Zou Hao, Xie Nan, Zhang Lu, Zhang Xin-Yu, Song Zheng-Ji, Dong Zhao-Ru, Hu Mei-Yu, Huang Xiao-Yong, Zhang Xiao-Wen, Ke Ai-Wu, Shi Guo-Ming
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China.
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
J Clin Pathol. 2017 Aug;70(8):677-683. doi: 10.1136/jclinpath-2016-204251. Epub 2017 Jan 17.
The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains poor in terms of overall survival (OS) and recurrence rate. Mortalin, a stress chaperone, has been reported to be involved in carcinogenesis and metastasis. However, its role in ICC has not been defined.
Mortalin expression in tumour samples from patients with ICC was examined by Western blot and immunohistochemistry, and correlation between its expression and clinicopathological features was assessed. In addition, invasion, migration proliferation and apoptosis, and the expression of epithelial-mesenchymal transition (EMT)-related markers in ICC cells were assessed after mortalin depletion. Finally, the prognostic significance of mortalin in patients with ICC was further evaluated by Kaplan-Meier and Cox regression analysis.
We provide evidence that expression of mortalin in human ICC tissues is higher than that in matched peritumoural tissues. The interference of mortalin expression inhibited the proliferation and invasion of ICC cells in vitro. Mechanistically, inhibition of mortalin expression in ICC cells upregulated E-cadherin expression and decreased vimentin and snail expression. Clinically, a high level of mortalin in ICC samples was associated with loss of E-cadherin, and increased expression of vimentin and snail. Patients with ICC and high mortalin expression had a shorter OS and a higher recurrence rate. Multivariate analysis revealed that mortalin overexpression was an independent prognostic indicator for patients with ICC.
Mortalin may promote cell proliferation and invasion via induction of EMT of ICC cells. A high level of mortalin may be used as a prognostic biomarker and therapeutic target for patients with ICC.
肝内胆管癌（ICC）患者的总生存期（OS）和复发率方面预后仍然较差。Mortalin，一种应激伴侣蛋白，据报道参与致癌作用和转移。然而，其在ICC中的作用尚未明确。
通过蛋白质免疫印迹法和免疫组织化学检测ICC患者肿瘤样本中Mortalin的表达，并评估其表达与临床病理特征之间的相关性。此外，在敲低Mortalin后，评估ICC细胞的侵袭、迁移、增殖和凋亡以及上皮-间质转化（EMT）相关标志物的表达。最后，通过Kaplan-Meier和Cox回归分析进一步评估Mortalin在ICC患者中的预后意义。
我们提供的证据表明，人类ICC组织中Mortalin的表达高于配对的癌旁组织。Mortalin表达的干扰在体外抑制了ICC细胞的增殖和侵袭。机制上，抑制ICC细胞中Mortalin的表达上调了E-钙黏蛋白的表达，并降低了波形蛋白和蜗牛蛋白的表达。临床上，ICC样本中高水平的Mortalin与E-钙黏蛋白的缺失、波形蛋白和蜗牛蛋白表达的增加相关。ICC且Mortalin高表达的患者OS较短且复发率较高。多变量分析显示，Mortalin过表达是ICC患者的独立预后指标。
Mortalin可能通过诱导ICC细胞的EMT促进细胞增殖和侵袭。高水平的Mortalin可作为ICC患者的预后生物标志物和治疗靶点。
