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Although much progress has been made in understanding cancer cellular metabolism adaptation, the co-regulations between genes of metabolism and cancer pathways and their interactions remain poorly characterized. Here, we applied gene co-expression network analysis to 1509 metabolic gene expression data generated from 120 HCC and 180 non-tumor human liver tissues by microarray. Our analyses reveal that metabolism genes can be classified into different co-expression modules based on their associations with HCC related traits. The co-regulation mechanism of the carbon metabolism genes in normal liver tissues was interrupted during the processes of carcinogenesis. In parallel, we performed RNAseq analysis of HCC and non-tumor human liver tissues, and identified a unique 22-carbon-metabolism-gene-signature of increased expression. This gene signature was further verified in multiple microarray data sets, and its prognostic value was also proven by HCC patients' survival data from TCGA. Additionally, the tumorigenic function of two representative genes, CS and ACSS1, were validated experimentally by cell growth and spheroid formation assays. The current study provides evidence for the reprogramming of the co-regulation network between carbon metabolism and cancer pathway genes in HCC. In addition, this study also reveals a unique 22-carbon-metabolism-gene-expression-signature in HCC. Strategies targeting these genes may represent new therapeutic approaches for HCC treatment.

Gene network analysis reveals a novel 22-gene signature of carbon metabolism in hepatocellular carcinoma