Currently, the controversy regarding the expression profile and function of BUB1B in different malignancies still exist. In this project, we aimed to explore the role and molecular mechanism of BUB1B in the progression of extrahepatic cholangiocarcinoma (ECC). The expression levels of BUB1B in human ECC were evaluated by immunohistochemistry, western blot, and real-time PCR. The role and mechanism of BUB1B in CCA cell proliferation and invasion were investigated in both in vitro and in vivo functional studies. To indicate the clinical significance, a tissue microarray was performed on 113 ECC patients, followed by univariate and multivariate analyses. The expression of BUB1B was increased in both human CCA tissues and CCA cells. Results from loss-of-function and gain-of-function experiments suggested that the inhibition of BUB1B decreased the proliferation and invasiveness of CCA cells in vitro and in vivo, while overexpression of BUB1B achieved the opposite effect. Furthermore, the activation of c-Jun N-terminal kinase-c-Jun (JNK)-c-Jun pathway was regulated by BUB1B. BUB1B regulated the proliferation and invasiveness of CAA cells in a JNK-c-Jun-dependent manner. Clinically, ECC patients with BUB1B high expression had worse overall survival and recurrence-free survival than those with BUB1B low expression. Multivariate analysis identified that BUB1B was an independent predictor for postoperative recurrence and overall survival of ECC patients. In conclusion, BUB1B promoted ECC progression via JNK/c-Jun pathways. These findings suggested that BUB1B could be a potential therapeutic target and a biomarker for predicting prognosis for ECC patients.

目前，关于BUB1B在不同恶性肿瘤中的表达谱和功能仍存在争议。在本项目中，我们旨在探索 BUB1B 在肝外胆管癌 (ECC) 进展中的作用和分子机制。通过免疫组织化学、蛋白质印迹和实时 PCR 评估 BUB1B 在人 ECC 中的表达水平。在体外和体内功能研究中研究了 BUB1B 在 CCA 细胞增殖和侵袭中的作用和机制。为了表明临床意义，对 113 名 ECC 患者进行了组织微阵列，然后进行了单变量和多变量分析。BUB1B 在人类 CCA 组织和 CCA 细胞中的表达均增加。功能丧失和功能获得实验的结果表明，BUB1B 的抑制降低了体外和体内 CCA 细胞的增殖和侵袭性，而 BUB1B 的过表达则达到了相反的效果。此外，c-Jun N 端激酶-c-Jun (JNK)-c-Jun 通路的激活受 BUB1B 调节。BUB1B 以 JNK-c-Jun 依赖性方式调节 CAA 细胞的增殖和侵袭性。临床上，BUB1B高表达的ECC患者比BUB1B低表达的ECC患者的总生存期和无复发生存期更差。多变量分析发现 BUB1B 是 ECC 患者术后复发和总生存的独立预测因子。总之，BUB1B 通过 JNK/c-Jun 通路促进 ECC 进展。