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

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.