Integration of chronological omics data reveals mitochondrial regulatory mechanisms during the development of hepatocellular carcinoma.

Abstract

Mitochondria participate in multiple functions in eukaryotic cells. Although disruption of mitochondrial function has been associated with energetic deregulation in cancer, the chronological changes in mitochondria during cancer development remain unclear. With the aim to assess the role of mitochondria throughout cancer development, we analyzed samples chronologically obtained from induced hepatocellular carcinoma (HCC) in rats. In our analyses, we integrated mitochondrial proteomic data, mitochondrial metabolomic data and nuclear genome transcriptomic data. We used pathway over-representation and weighted gene co-expression network analysis (WGCNA) to integrate expression profiles of genes, miRNAs, proteins and metabolite levels throughout HCC development. Our results show that mitochondria are dynamic organelles presenting specific modifications in different stages of HCC development. We also found that mitochondrial proteomic profiles from tissues adjacent to nodules or tumor are determined more by the stage of HCC development than by tissue type, and we evaluated two models to predict HCC stage of the samples using proteomic profiles. Finally, we propose an omics integration pipeline to massively identify molecular features that could be further evaluated as key regulators, biomarkers or therapeutic targets. As an example, we show a group of miRNAs and transcription factors as candidates, responsible for mitochondrial metabolic modification in HCC.