Ubiquitin-specific protease 11 serves as a marker of poor prognosis and promotes metastasis in hepatocellular carcinoma

Abstract

Ubiquitin-specific protease 11 (USP11) is a deubiquitinating enzyme that exerts its biological functions by regulating multiple signaling pathways such as p53, NF-κB, TGF-β, and Hippo. A large body of evidence supports a link between UPS11 and tumorigenesis. However, the clinical significance and biological function of USP11 in hepatocellular carcinoma (HCC) remains unclear. Here, USP11 expression was assessed by immunohistochemistry in a pilot series of 71 HCC clinical samples, and the association between USP11 expression and clinicopathological features and overall survival time was analyzed. The cytoplasmic expression rate of USP11 was higher in non-cancerous tissue than that in cancer tissue (36.6 vs. 12.7%, P = 0.001), whereas the nuclear expression rate of USP11 was lower in non-cancerous tissue (5.6 vs. 69.0%, P < 0.001). USP11 expression level was higher in tumor than that in non-tumor tissue (P < 0.001). Chi-square analysis of variances suggested that USP11 expression was associated with vascular invasion (P = 0.033), differentiation (P = 0.027), tumor number (P = 0.009), and recurrence (P = 0.036). USP11 expression was also associated with shorter overall survival time (P = 0.001) by log-rank test. Unconditional logistic regression analysis with multiple covariates indicated that high USP11 expression was associated with a 2.96-fold increase in the risk of death compared with low USP11 levels (P = 0.041) and acted as an independent predictor of overall survival. HCC patients with simultaneously high USP11 and alpha-fetoprotein expression had an adjusted 5-fold higher risk of all-cause-related death (P = 0.006). Moreover, in vitro and in vivo experiments confirmed that USP11 could promote the migration and invasion of HCC cell. Overall, we suggest that USP11 promotes HCC cell metastasis, and we provide the first evidence of the prognostic significance of USP11 expression in HCC, which suggests that USP11 is a promising therapeutic target for the treatment of HCC.

Identification and Characterization of USP7 Targets in Cancer Cells

“…For example, USP7 has been reported to associate with USP11, leading to regulation of polycomb repressive complex 1 (PRC1), but little is known about the mechanism of this interaction 36 , 37 . Like USP7, USP11 appears to have multiple cancer-associated roles, that could either promote or suppress oncogenesis 38 – 42 and therefore a better understanding of the USP7-USP11 interaction is warranted. An interaction of USP7 with the ATM-dependent phosphatase PPM1G has also been reported but not well characterized 36 , 43 .…”

Identification and Validation of Ubiquitin-Specific Proteases as a Novel Prognostic Signature for Hepatocellular Carcinoma

“…Besides of regulating malignant behaviors, USPs were also considered as prognostic markers. Previous studies suggested that USP4, USP7, USP11, and USP33 were correlated with poor survival of HCC patients (13)(14)(15)(16).…”

Long noncoding RNA lnc-DILC stabilizes PTEN and suppresses clear cell renal cell carcinoma progression

“…PTEN activates the transcription of USP11 by the PI3K/FOXO pathway to enhance its own stability in prostate cancer cell line [26]. Nevertheless, USP11 functions as an oncogene in liver cancer to promote growth and metastasis [49]. Here, we showed that USP11 involved in lnc-DILC-mediated stabilization of PTEN, suggesting that USP11 may act as a tumor suppressor in ccRCC.…”