<p>Down-regulation of USP8 Inhibits Cholangiocarcinoma Cell Proliferation and Invasion</p>

Abstract

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 upregulate 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.

USP8 is a Novel Therapeutic Target in Melanoma Through Regulating Receptor Tyrosine Kinase Levels

“…The oncogenic role of USP8 in other cancers, such as lung cancer, cervical cancer and Cholangiocarcinoma, have been reported. 6–8 Our work together with the previous reports suggest that USP8 is a novel therapeutic target for cancer.…”

“…5 Ubiquitin-specific protease 8 (USP8), one of USP family member, has been recently revealed to play important roles in cancer progression, metastasis and drug resistance. [6][7][8][9] USP8 interacts with Cdc25, Nrdp1, ErbB2 and epithelial growth factor receptor (EGFR), which are all clinically relevant cancer targets. USP8 knockout mice display significant growth retardation and marked downregulation of several receptor tyrosine kinases (RTKs), including EGFR, c-Met and ErbB3.…”

USP5 Promotes Uterine Corpus Endometrial Carcinoma Cell Growth and Migration via mTOR/4EBP1 Activation

“…25 Oncogenic function of USP8 is also observed in gastric cancer, cholangiocarcinoma, and breast cancer. [26][27][28] Apart from them, a growing body of evidence has demonstrated the tumor-promoting role of USP5 in different cancer types. 8,10,11,[13][14][15] And in this study, we found that it was also the case in UCEC.…”

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

“…The depletion of USP8 promotes intrinsic apoptosis by suppressing AKT activity in cholangiocarcinoma (CCA) [ 79 ]. USP8 promotes both the stabilization and destabilization of c-FLIP, an anti-apoptotic protein.…”