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Down-regulation of USP8 Inhibits Cholangiocarcinoma Cell Proliferation and Invasion

Authors Jing X, Chen Y, Chen Y, Shi G, Lv S, Cheng N, Feng C, Xin Z, Zhang L, Wu J

Received 14 October 2019

Accepted for publication 15 March 2020

Published 24 March 2020 Volume 2020:12 Pages 2185—2194

DOI https://doi.org/10.2147/CMAR.S234586

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Sanjeev Srivastava


Xu Jing, 1 Yingjie Chen, 1 Ye Chen, 2 Guangyan Shi, 1 Shuanghao Lv, 1 Nana Cheng, 1 Chaolin Feng, 1 Zhen Xin, 1 Liping Zhang, 3 Jing Wu 4

1Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, People’s Republic of China; 3The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 4Department of Pharmacy, The Second Hospital of Shandong University, Jinan, People's Republic of China

Correspondence: Jing Wu
Department of Pharmacy, The Second Hospital of Shandong University, No. 247 Beiyuan West Road, Jinan 250033, People’s Republic of China
Email wujing19830603@126.com

Liping Zhang
The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19 Renmin Road, Zhengzhou 450000, People’s Republic of China
Email weier_528@163.com

Objective: Cholangiocarcinoma is the second most common primary hepatobiliary malignancy with high incidence and recurrence rate. Ubiquitin-specific protease 8 (USP8) is recently reported to be involved in tumor progression. Herein, we aimed to investigate the effects of USP8 on the growth and metastasis abilities of cholangiocarcinoma cells.
Methods: The siRNA interference was used to knock down USP8 in cholangiocarcinoma cell lines QBC939 and RBE; Hucct-1 cells were transfected with pcDNA3.1-USP8 to up-regulate its expression. The effects of USP8 on cholangiocarcinoma were detected by cell function assays. We analyzed the expressions of USP8, Bcl2, Bax, cleaved caspase-3, cleaved caspase-9, Akt, p-Akt, Cyclin D1 and P70S6K by Western blot analysis.
Results: We demonstrated that knockdown of USP8 significantly inhibited the proliferation, migration and invasion of QBC939 and RBE cells in vitro, while USP8 overexpression showed significant promoting effects on Hucct-1 cells. Moreover, silencing of USP8 also promoted apoptosis in cholangiocarcinoma cells by regulating the Bcl-2/Bax axis and Caspase cascade; up-regulation of USP8 decreased apoptosis in Hucct-1 cells. Importantly, knockdown of USP8 inhibited activation of the Akt signaling pathway by decreasing the phosphorylation level of Akt and up-regulated p53 expression, while USP8 overexpression increased activation of the Akt signaling pathway in Hucct-1 cells. Further, IGF-1 could reverse the inhibitory effects of USP8 knockdown on the Akt signaling pathway and the proliferation of QBC939 and RBE cells.
Conclusion: Taken together, our findings suggest that USP8 exerts an oncogenic role in the progression of cholangiocarcinoma and may be a potential therapeutic target for cholangiocarcinoma treatment.

Keywords: cholangiocarcinoma, ubiquitin-specific protease 8, Akt signaling pathway

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