Abstract
Ubiquitin-specific protease 22 (USP22) removes ubiquitin from histones, thus regulating gene transcription. The expression frequency and expression levels of USP22 were significantly higher in hepatocellular carcinoma (HCC) than in normal liver tissues. High USP22 expression in HCC was significantly correlated with clinical stage and tumor grade. Kaplan-Meier analysis showed that elevated USP22 expression predicted poorer overall survival and recurrence-free survival. High USP22 expression was also associated with shortened survival time in patients at advanced tumor stages and with high grade HCC. Multivariate analyses revealed that USP22 expression is an independent prognostic parameter in HCC. These findings provide evidence that high USP22 expression might be important in tumor progression and serves as an independent molecular marker for poor HCC prognosis. Thus, USP22 overexpression identifies patients at high risk and represents a novel therapeutic molecular target for this tumor.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor worldwide and causes approximately 600,000 deaths globally each year [1]
Ubiquitin-specific protease 22 (USP22) expression was analyzed in seven established human HCC cell lines (Bel-7402, HepG2, HuH-7, SK-Hep-1, Hep3B, QGY-7701 and SMMC-7721) and a normal hepatic cell line LO2 using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay
Based on the semi-quantitative RT-PCR analysis of seven pairs of HCC and normal adjacent liver tissues, we found that USP22 mRNA was overexpressed in HCC (Fig. 2A); this finding was confirmed using quantitative RT-PCR analysis (Fig. 2C)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor worldwide and causes approximately 600,000 deaths globally each year [1]. Because tumorigenesis and tumor progression in hepatic cells are caused by multiple genetic alterations, a single molecule targeting therapy has yet to be discovered. USP22 is an important www.impactjournals.com/oncotarget subunit of the human Spt-Ada-Gcn acetyltransferase (hSAGA) transcriptional cofactor complex, which is required for activator-driven transcription and cell cycle progression [4]. Within the hSAGA complex, USP22 removes ubiquitin from histone H2B, regulating the transcription of downstream genes that are related to epigenetic alteration and cancer progression. USP22 is required for the proper functioning of MYC, which is widely believed to play a significant role in regulating the tumor cell cycle and tumor invasion [4, 5]. Recent studies have demonstrated that USP22 can inhibit the transcription of the p21 gene by de-ubiquitinating the transcriptional regulator FBP1, leading to cell proliferation and tumorigenesis [6]. The clinical significance of USP22 expression in patients with HCC and the role of USP22 in a HCC cell line have not yet been investigated
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