Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand.
Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
Naunyn Schmiedebergs Arch Pharmacol. 2021 Oct;394(10):2049-2059. doi: 10.1007/s00210-021-02123-0. Epub 2021 Jul 20.
Northeast Thailand has the highest incidence of cholangiocarcinoma (CCA) in the world. The lack of promising diagnostic markers and appropriate therapeutic drugs is the main problem for metastatic stage CCA patients who have a poor prognosis. N-cadherin, a cell adhesion molecule, is usually upregulated in cancers and has been proposed as an important mediator in epithelial-mesenchymal transition (EMT), one of the metastasis processes. Additionally, it has been shown that arctigenin, a seed isolated compound from Arctium lappa, can inhibit cancer cell progression via suppression of N-cadherin pathway. In this study, we investigated the protein expression of N-cadherin and its correlation with clinicopathological data of CCA patients, as well as the impact of arctigenin on KKU-213A and KKU-100 CCA cell lines and its underlying mechanisms. Immunohistochemistry results demonstrated that high expression of N-cadherin was significantly associated with severe CCA stage (p = 0.027), and shorter survival time (p = 0.002) of CCA patients. The mean overall survival times between low and high expression of N-cadherin were 31.6 and 14.8 months, respectively. Wound healing assays showed that arctigenin significantly inhibited CCA cell migration by downregulating N-cadherin whereas upregulating E-cadherin expression. Immunocytochemical staining revealed that arctigenin suppressed the expression of N-cadherin in both CCA cell lines. Furthermore, flow cytometry and western blot analysis revealed that arctigenin significantly reduced CCA cell viability and induced apoptosis via the Bax/Bcl-2/caspase-3 pathway. This research supports the use of N-cadherin as a prognostic marker for CCA and arctigenin as a potential alternative therapy for improving CCA treatment outcomes.
泰国东北部是世界上胆管癌（CCA）发病率最高的地区。缺乏有前途的诊断标志物和适当的治疗药物是转移性 CCA 患者的主要问题，这些患者的预后较差。N-钙黏蛋白是一种细胞黏附分子，通常在癌症中上调，并被提议作为上皮-间充质转化（EMT）的重要介质之一，EMT 是转移过程之一。此外，已经表明，牛蒡子苷元是牛蒡子中的一种种子分离化合物，可以通过抑制 N-钙黏蛋白途径来抑制癌细胞的进展。在这项研究中，我们研究了 N-钙黏蛋白的蛋白表达及其与 CCA 患者临床病理数据的相关性，以及牛蒡子苷元对 KKU-213A 和 KKU-100 CCA 细胞系的影响及其潜在机制。免疫组织化学结果表明，N-钙黏蛋白的高表达与 CCA 严重分期（p=0.027）显著相关，并且与 CCA 患者的生存时间较短（p=0.002）显著相关。N-钙黏蛋白低表达和高表达的 CCA 患者的总平均生存时间分别为 31.6 个月和 14.8 个月。划痕愈合试验表明，牛蒡子苷元通过下调 N-钙黏蛋白显著抑制 CCA 细胞迁移，而上调 E-钙黏蛋白的表达。免疫细胞化学染色显示，牛蒡子苷元抑制了两种 CCA 细胞系中 N-钙黏蛋白的表达。此外，流式细胞术和 Western blot 分析表明，牛蒡子苷元通过 Bax/Bcl-2/caspase-3 途径显著降低 CCA 细胞活力并诱导细胞凋亡。这项研究支持将 N-钙黏蛋白作为 CCA 的预后标志物，并将牛蒡子苷元作为改善 CCA 治疗结果的潜在替代治疗方法。
