Regulation Network and Prognostic Significance of Aldo-Keto Reductase (AKR) Superfamily Genes in Hepatocellular Carcinoma

PURPOSE: The aldo-keto reductase (AKR) superfamily members have been proposed with multiple roles in various tumors. Here, a comprehensive analysis on the integral role of AKR genes was conducted to evaluate the expression profile, regulation network, and prognostic significance in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Transcriptome datasets of HCC were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Univariate and multivariate Cox regression analyses were used to build a novel risk score model, and then were further used to identify independent prognostic factors for overall survival (OS) of HCC. A prognostic nomogram was developed and validated. The expression of these critical AKR members was also evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry in HCC specimens. RESULTS: Eight differentially expressed AKR genes were identified in HCC. The dysregulation of most AKR genes was negatively correlated with DNA methylation, and a regulation network with transcription factors (TFs) was also established. Then, three critical AKR genes (AKR1B10, AKR1D1, and AKR7A3) were screened out to build a novel risk score model. Worse OS was observed in high-risk patients. Besides, a prognostic nomogram based on the model was further established and validated in both the TCGA and GSE14520 cohorts, which showed superior performance in predicting the OS of HCC patients. Notably, close correlations were identified between the risk score and tumor immune microenvironment, somatic mutation profiles, and drug susceptibilities of HCC. Finally, the upregulated AKR1B10 and downregulated AKR1D1 and AKR7A3 were further verified in HCC tumor and adjacent tissues from our institution. CONCLUSION: The dysregulated AKR genes could be mediated by DNA methylation and TFs in HCC. The risk model established with superior prognostic performance further suggested the significant role of AKR genes involved in the progression of HCC.