Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, Shandong, China.
Department of Outpatient, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266003, Shandong, China.
Dig Dis Sci. 2019 Oct;64(10):2843-2853. doi: 10.1007/s10620-019-05609-3. Epub 2019 Apr 4.
Cholangiocarcinoma is one of the most deadly malignant tumors characterized by a tendency of local invasiveness and metastasis at the early phase, high recurrence rate, and difficulty in treatment. Alpha7-nicotinic acetylcholine receptor (α7-nAChR) is highly expressed in a variety of tumors, including cholangiocarcinoma, and may promote tumor progression, but the mechanisms are largely unknown.
Our study is the first to expound upon the role that α7-nAChR plays in cholangiocarcinoma.
We assessed 50 human cholangiocarcinoma tissue samples and 20 normal biliary samples using immunohistochemical staining to find the correlation between α7-nAChR expression and clinicopathological characteristics. We used human cholangiocarcinoma cell lines QBC939 and RBE and α7-nAChR gene knockdown RBE cell lines generated by shRNA lentivirus transfection to investigate the biological functions of α7-nAChR in proliferation, apoptosis, migration, and invasiveness in vitro. Further, western blotting was used to detect apoptosis and epithelial-mesenchymal transition (EMT)-related signaling proteins. Cholangiocarcinoma xenografts in nude mice were used for tumorigenicity assays in vivo.
The expression of α7-nAChR was high in cholangiocarcinoma tissues and was closely related to a shorter survival time in patients. α7-nAChR knockdown decreased cell proliferation ability, increased early apoptosis, and weakened cell migration and invasion. Apoptosis-related proteins and components of the EMT process were altered after α7-nAChR knockdown. Moreover, nude mice xenograft experiments confirmed that α7-nAChR could promote cholangiocarcinoma in vitro.
Overexpression of α7-nAChR induces cholangiocarcinoma progression by blocking apoptosis and promoting the EMT process. As an effective molecular biomarker and prognostic factor, α7-nAChR is a promising therapeutic target in cholangiocarcinoma.
胆管癌是一种最致命的恶性肿瘤之一，其特点是早期局部侵袭和转移倾向、高复发率以及治疗困难。α7-烟碱型乙酰胆碱受体（α7-nAChR）在多种肿瘤中高度表达，包括胆管癌，可能促进肿瘤进展，但机制在很大程度上尚不清楚。
我们的研究首次阐述了α7-nAChR 在胆管癌中的作用。
我们使用免疫组织化学染色评估了 50 个人胆管癌组织样本和 20 个正常胆管样本，以发现 α7-nAChR 表达与临床病理特征之间的相关性。我们使用人胆管癌细胞系 QBC939 和 RBE 以及通过 shRNA 慢病毒转染生成的 α7-nAChR 基因敲低 RBE 细胞系，在体外研究 α7-nAChR 在增殖、凋亡、迁移和侵袭中的生物学功能。进一步使用 Western blot 检测凋亡和上皮-间充质转化（EMT）相关信号蛋白。使用裸鼠胆管癌异种移植进行体内肿瘤发生测定。
α7-nAChR 在胆管癌组织中的表达较高，与患者生存时间较短密切相关。α7-nAChR 敲低降低了细胞增殖能力，增加了早期凋亡，并减弱了细胞迁移和侵袭。α7-nAChR 敲低后，凋亡相关蛋白和 EMT 过程的组成部分发生改变。此外，裸鼠异种移植实验证实了 α7-nAChR 可以促进胆管癌的发生。
α7-nAChR 的过表达通过阻断凋亡和促进 EMT 过程诱导胆管癌进展。作为一种有效的分子生物标志物和预后因素，α7-nAChR 是胆管癌有前途的治疗靶点。
