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

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

doi:10.18632/oncotarget.13219

Abstract

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.

Highlights

The majority of colorectal cancer (CRC) metastases localize to the liver, and surgical resection is the most effective therapy for liver metastases of CRC (CRCLM)
The results showed that USP33 knock-down can significantly promote cell migration, while USP33 overexpression exhibited a down-regulation effect. (E) Cell proliferation was detected by a MTT-assay, showing how USP33 expression was negatively correlated with cell proliferation. (F) Silencing of USP33 can increase the cell invasive capacity under Stromal cell-derived factor-1 (SDF-1) stimulation, whereas USP33 overexpression demonstrated the opposite regulation
Our results demonstrated that USP33 knock-down significantly prolonged SDF-1 induced ERK signaling in colorectal cancer cells by regulating the ubiquitination status of β-arrestin2

Summary

Introduction

The majority of CRC metastases localize to the liver, and surgical resection is the most effective therapy for liver metastases of CRC (CRCLM). For those patients, the biological features of both CRC and CRCLM are important in evaluating the clinical outcome. Even for the patients who underwent resection of CRC and CRCLM, 50–75% of cases may develop recurrence, especially intrahepatic recurrence [3, 4]. CRCLM is important to improve the clinical outcome of these advanced cases. For the patients who were diagnosed at a localized stage (less than 40% of all cases), the 5-year OS can be more than 90%. About 20% of patients have distant metastasis at the time of diagnosis, with the 5-year OS less than 15% [1]

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Results

Conclusion