Abstract
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.
Highlights
An unique characteristic of cancer is altered energy metabolism, a result of cancer cell genetic instability and/or effects of the tumor microenvironment [1]
To investigate metabolic gene sets that are associated with the hepatocellular carcinoma (HCC) status and their clinical traits, we applied Weighted Gene Coexpression Network Analysis (WGCNA), which defines transcriptional modules based on Pearson correlation and determines relationship between these modules and different clinical traits [7]
Our results show that 22 out of the 106 genes were overexpressed in HCC compared to the non-tumor liver tissues (Supplementary Table S4)
Summary
An unique characteristic of cancer is altered energy metabolism, a result of cancer cell genetic instability and/or effects of the tumor microenvironment [1]. Mitochondrial respiration is required for tumor progression [4]. These carbon metabolic alterations can provide cancer cells energy and substances used for synthesis of macromolecules, which are essential for cell proliferation and replication. The metabolic switch may confer a selective growth advantage that drives tumorigenesis. All of these aspects underscore the importance of metabolic reprogramming, a common phenomenon observed across multiple types of cancers including hepatocellular carcinoma (HCC) [2, 5]
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