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

Purpose: Ubiquitin-specific proteases (USPs), as a sub-family of deubiquitinating enzymes (DUBs), are responsible for the elimination of ubiquitin-triggered modification. USPs are recently correlated with various malignancies. However, the expression features and clinical significance of USPs have not been systematically investigated in hepatocellular carcinoma (HCC). Methods: Genomic alterations and expression profiles of USPs were investigated in CbioPortal and The Cancer Genome Atlas (TCGA) LIHC dataset. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were conducted to establish a risk signature for HCC prognosis in TCGA LIHC cohort. Subsequently, Kaplan-Meier analysis, receiver operating characteristic (ROC) curves and univariate / multivariate analyses were performed to evaluate the prognostic significance of the risk signature in TCGA LIHC and international cancer genome consortium (ICGC) cohorts. Furthermore, we explored the alterations of the signature genes during hepatocarcinogenesis and HCC progression in GSE889377. Results: Genomic alterations and overexpression of USPs were observed in HCC tissues. The consensus analysis indicated that the USPs-overexpressed sub-Cluster was correlated with aggressive characteristics and poor prognosis. Cox regression with LASSO algorithm identified a risk signature formed by 8 USPs for HCC prognosis. High risk group stratified by the signature score was correlated with advanced tumor stage and poor survival HCC patients in TCGA LIHC cohort. In addition, the 8-USPs based signature could also robustly predict overall survival of HCC patients in ICGC(LIRI-JP) cohort. In addition, gene sets enrichment analysis (GSEA) showed that the high-risk score was associated with tumor-related pathways. According to the observation in GSE889377, USP39 expression was dynamically increased with hepatocarcinogenesis and HCC progression. Further co-concurrence analysis indicated that USP39 might promote HCC by regulating cell-cycle- and proliferation- related genes. Conclusion: The current study provided a USPs-based signature, highlighting its robust prognostic significance and targeted value for HCC treatment.