Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor type, ranking as the third leading cause of all cancer-related deaths in the world. The post-surgical 5-year survival rate is low, largely due to the high recurrence rate. Therefore, the identification of target molecules that control the biological characteristics of HCC is of great importance. Ubiquitin-specific protease 22 (USP22) is a newly discovered deubiquitinating enzyme and is a cancer stem cell marker that plays a role in tumorigenesis, therapy resistance and cell cycle progression. Survivin is a member of the inhibitor of apoptosis protein (IAP) family and is known to function either as an inhibitor for apoptosis or as a regulator of cell division. Levels of survivin are correlated with the aggressiveness of tumors and a poor prognosis in various cancers including HCC. In the present study, we examined the USP22 expression and its association with survivin expression and clinicopathological features in HCC. First, we examined the expression of USP22 and survivin in 151 HCC cases by immunohistochemistry. High expression of USP22 and survivin was frequently observed in HCC cases, in comparison with normal adjacent liver tissues. Expression of USP22 and survivin was well correlated with malignant behavior including tumor size, stage and differentiation in HCC cases. Importantly, HCC patients with high expression of USP22 and survivin showed poor prognosis. USP22 expression was well correlated with survivin expression in HCC cases. This correlation was confirmed in HCC cell lines and tissues by RT-PCR and western blot analysis. Next, to investigate the biological role of USP22 in HCC, we examined the effect of USP22 knockdown on the cell growth and the expression of cell cycle-related protein including survivin in HCC cells. USP22 siRNA suppressed cell growth. Moreover, USP22 siRNA decreased survivin expression together with upregulation of CDK inhibitor, p21 and downregulation of cyclinB. These findings suggest that USP22 may be involved in HCC progression in cooperation with survivin. We suggest that USP22 can be useful as a new prognostic marker and therapeutic target in HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor type, ranking as the third leading cause of all cancer-related deaths in the world [1,2]
We examined the expression of Ubiquitin-specific protease 22 (USP22) and survivin in 30 normal adjacent liver samples and 151 HCC tissues by immunohistochemistry
We found that 53.0% of the 151 HCC cases showed high expression of USP22 by immunohistochemistry
Summary
Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor type, ranking as the third leading cause of all cancer-related deaths in the world [1,2]. Since tumorigenesis and tumor progression of hepatic cells are the result of multiple genetic alterations, a single molecule targeting therapy has yet to be discovered. USP22 is considered to be a cancer stem cell marker that induces therapy resistance, tumor aggressiveness and metastatic dissemination; its expression is associated with a poor outcome in various cancers including colon, breast and liver cancer [5,6,7,8,9]. USP22 is an enzymatic subunit of the hSAGA transcriptional cofactor complex, which is required for activator-driven transcription, cell cycle progression and tumorigenesis [5,6]. USP22 is required for the transcription of target genes regulated by the MYC oncoprotein and other sequence-specific activators that
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