RNA sequencing analysis of hepatocellular carcinoma identified oxidative phosphorylation as a major pathologic feature

Abstract

Abstract Dysregulation of expression of functional genes and pathways plays critical roles in the etiology and progression of hepatocellular carcinoma (HCC). Next generation‐based RNA sequencing (RNA‐seq) offers unparalleled power to comprehensively characterize HCC at the whole transcriptome level. In this study, 17 fresh‐frozen HCC samples with paired non‐neoplastic liver tissue from Caucasian patients undergoing liver resection or transplantation were used for RNA‐seq analysis. Pairwise differential expression analysis of the RNA‐seq data was performed to identify genes, pathways, and functional terms differentially regulated in HCC versus normal tissues. At a false discovery rate (FDR) of 0.10, 13% (n = 4335) of transcripts were up‐regulated and 19% (n = 6454) of transcripts were down‐regulated in HCC versus non‐neoplastic tissue. Eighty‐five Kyoto Encyclopedia of Genes and Genomes pathways were differentially regulated (FDR, <0.10), with almost all pathways (n = 83) being up‐regulated in HCC versus non‐neoplastic tissue. Among the top up‐regulated pathways was oxidative phosphorylation (hsa00190; FDR, 1.12E‐15), which was confirmed by Database for Annotation, Visualization, and Integrated Discovery (DAVID) gene set enrichment analysis. Consistent with potential oxidative stress due to activated oxidative phosphorylation, DNA damage‐related signals (e.g., the up‐regulated hsa03420 nucleotide excision repair [FDR, 1.14E‐04] and hsa03410 base excision repair [FDR, 2.71E‐04] pathways) were observed. Among down‐regulated genes (FDR, <0.10), functional terms related to cellular structures (e.g., cell membrane [FDR, 3.05E‐21] and cell junction [FDR, 2.41E‐07], were highly enriched, suggesting compromised formation of cellular structure in HCC at the transcriptome level. Interestingly, the olfactory transduction (hsa04740; FDR, 1.53E‐07) pathway was observed to be down‐regulated in HCC versus non‐neoplastic tissue, suggesting impaired liver chemosensory functions in HCC. Our findings suggest oxidative phosphorylation and the associated DNA damage may be the major driving pathologic feature in HCC.