Research Papers:

Prognostic significance of USP33 in advanced colorectal cancer patients: new insights into β-arrestin-dependent ERK signaling

Hongda Liu, Qun Zhang, Kangshuai Li, Zheng Gong, Zhaochen Liu, Yunfei Xu, Mary Hannah Swaney, Kunhong Xiao and Yuxin Chen _

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Oncotarget. 2016; 7:81223-81240. https://doi.org/10.18632/oncotarget.13219

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Hongda Liu1,2,3, Qun Zhang4, Kangshuai Li1, Zheng Gong2, Zhaochen Liu1, Yunfei Xu1, Mary Hannah Swaney5, Kunhong Xiao3, Yuxin Chen1

1Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, China

2Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, Shandong 250012, China

3Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA

4Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China

5Pennsylvania State University, University Park, Pennsylvania, 16802, USA

Correspondence to:

Yuxin Chen, email: [email protected]

Keywords: β-arrestin2, CRCLM, CXCR4, ubiquitination, USP33

Received: August 15, 2016     Accepted: October 14, 2016     Published: November 08, 2016


Patients with liver metastases of colorectal cancer (CRCLM) have a poorer prognosis compared to colorectal cancer (CRC) patients in local stage. Evaluating the recurrence and overall survival of advanced patients is critical in improving disease treatment and clinical outcome. Here we investigated the expression pattern of USP33, a deubiquitinating enzyme, in both primary CRC tissues and liver metastases tissues. Univariate and multivariate analyses identified that low expression of USP33 in CRCLM tissues indicated high recurrence risk and poor overall prognosis. Overexpression of USP33 can significantly inhibit cell proliferation, migration, and invasion. On the other hand, USP33 knock-down promoted cell proliferation and invasion under SDF-1 stimulation; whereas dynasore (an internalization inhibitor) pretreatment in USP33 silencing cells showed a distinct antipromoting effect, revealing the participation of CXCR4 internalization in regulating tumor progress. Further results verified that USP33 can deubiquitinate β-arrestin2, subsequently block the internalization of SDF-1-stimulated CXCR4, and disrupt β-arrestin-dependent ERK activation. The existence and functions of β-arrestin-dependent signaling have been previously determined in several Gs-coupled receptors, such as β2-adrenergic receptor and angiotensin receptor subtype 1a; however, little is known about this in Gi-coupled receptors. Our study not only established USP33 as a novel prognosis biomarker in advanced CRCLM patients, but also highlighted the significance of β-arrestin-dependent ERK signaling in cancer development.

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