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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


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

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

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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