USP33 is an integrin α6 deubiquitinase and promotes esophageal squamous cell carcinoma cell migration and metastasis.

PURPOSE

The deubiquitinating enzymes (DUBs) have been linked to cancer initiation and progression. Although ubiquitin-specific protease 33 (USP33) represents a significant factor in regulating various tumor cell behaviors, its specific biological functions and precise mechanisms in esophageal squamous cell carcinoma (ESCC) progression remain unclear.

METHODS

The expressions of USP33 mRNA in GEO databases, clinical ESCC samples, and USP33 protein were analyzed using bioinformatics, RT-PCR, and immunohistochemistry, respectively. Using Kaplan-Meier survival curves, the log-rank test was used to determine the cumulative survival rate. Western blotting was used to determine indicated protein expression. The cell biological functions were evaluated by cell growth assay, transwell, cell adhesion, and cell spreading assay, respectively. The interaction between USP33 and integrins was detected by immunoprecipitation, and the deubiquitination was performed by deubiquitination assay. The metastatic ability was checked by tail vein injection.

RESULTS

A significant positive correlation was found between USP33 expression and clinical TNM stage, T classification, and poor prognosis in patients with ESCC. USP33 promoted laminin-dependent adhesion, spreading, and migration of ESCC cells but not their proliferation. Mechanistically, USP33 mediates cell migration through binding, deubiquinating, and stabilizing integrin α6. USP33 knockdown could inhibit ESCC cell migration and metastasis majorly through integrin α6.

CONCLUSION

This study reveals a novel mechanism of USP33 in promoting laminin-dependent ESCC cell migration and metastasis through integrin α6, suggesting that USP33 may be a promising target for treating ESCC.