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.
Highlights
These authors contributed : Sheng Zhang, Chengrong Xie, Honghe Li.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the second leading cause of cancer-related mortality [1]
Location of Ubiquitin-specific protease 11 (USP11) in HCC and LO2 cells, and the results showed that USP11 was mainly located in HCC cell nucleus, while in LO2 cells, USP11 was mainly located in the cytoplasm (Supplementary Figure S1)
USP11 was expressed in the nucleus in 5.6% (4/71) of non-cancerous tissue, whereas nuclear expression was significantly higher in HCC samples at 69.0% (49/71) (P < 0.001, Fig. 2f)
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the second leading cause of cancer-related mortality [1]. Because of its aggressive nature and a high rate of recurrence and metastasis, the prognosis and survival of HCC patients remains disappointing [2]. Post-translational modification of proteins by covalent attachment of ubiquitin via the E1–E2–E3 ubiquitin ligation enzyme cascade is involved in the regulation of many essential cellular processes [3]. E3 ubiquitin ligases select substrates for ubiquitin conjugation, which is reversed by the action of deubiquitinating enzymes (DUB) [4,5,6]. Ubiquitin-specific protease 11 (USP11) is a DUB that belongs to a USP family and harbors two internal ubiquitin-like domains and an N-terminal domain present in USPs [6]
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