BUB1B promotes extrahepatic cholangiocarcinoma progression via JNK/c-Jun pathways

Chen Yu Jiao,Dong Wang,Yao Dong Zhang,Sheng Han,Jiang Chang,Xiang Cheng Li,Chang Xian Li,Xuehao Wang,Qin Chao Feng,Wang Jie Jiang

doi:10.1038/s41419-020-03234-x

Abstract

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.

Highlights

Cholangiocarcinoma (CCA), described as a malignancy that arises from the epithelial cells of the bile duct, is the second most common primary hepatobiliary malignancy[1]
BUB1B was upregulated in CCA tissues and cell lines To explore the expression profiles of BUB1B in CCA, we first examined the expression in CCA patients from a public The Cancer Genome Atlas (TCGA) database and found that BUB1B was overexpressed in CCA tissues compared to para-tumor (Fig. 1A)
The results showed that the expression level of BUB1B was upregulated in extrahepatic cholangiocarcinoma (ECC) tissues compared with their corresponding para-tumor tissues (Fig. 1B)

Summary

Introduction

Cholangiocarcinoma (CCA), described as a malignancy that arises from the epithelial cells of the bile duct, is the second most common primary hepatobiliary malignancy[1]. CCA can be divided into intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) according to the tumor location in the biliary tree. ECC is the most common CCA accounting for ~75% of all CCA2. Complete surgical resection remains the first choice for the treatment of CCA patients. The rates of resectability and the long-term outcome after these therapies are less than satisfactory because of the high post-surgical recurrence[3,4,5]. A clearer understanding of CCA growth and metastasis mechanisms is urgently necessary to find the potential therapeutic targets for CCA

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Conclusion