Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice

Abstract

Activation of the Ras/MAPK pathway is prevalently involved in the occurrence and development of hepatocellular carcinoma (HCC). However, its effects on the deregulated cellular metabolic processes involved in HCC in vivo remain unknown. In this study, a mouse model of HCC induced by hepatocyte-specific expression of the Hras12V oncogene was investigated using an integrative analysis of metabolomics and transcriptomics data. Consistent with the phenotype of abundant lipid droplets in HCC, the lipid biosynthesis in HCC was significantly enhanced by (1) a sufficient supply of acetyl-CoA from enhanced glycolysis and citrate shuttle activity; (2) a sufficient supply of NADPH from enhanced pentose phosphate pathway (PPP) activity; (3) upregulation of key enzymes associated with lipid biosynthesis; and (4) downregulation of key enzymes associated with bile acid biosynthesis. In addition, glutathione (GSH) was significantly elevated, which may result from a sufficient supply of 5-oxoproline and L-glutamate as well as an enhanced reduction in the process of GSSG being turned into GSH by NADPH. The high level of GSH along with elevated Bcl2 and Ucp2 expression may contribute to a normal level of reactive oxygen species (ROS) in HCC. In conclusion, our results suggest that the lipid metabolism, glycolysis, PPP, tricarboxylic acid (TCA) cycle, citrate shuttle activity, bile acid synthesis, and redox homeostasis in the HCC induced by ras oncogene are significantly perturbed, and these altered metabolic processes may play crucial roles in the carcinogenesis, development, and pathological characteristics of HCC.

This study provides integrative analysis of metabolomics and transcriptomics data for mouse HCC induced by the ras oncogene. The enhanced glycolysis, citrate shuttle, pentose phosphate pathway, and expression of lipid biosynthesis-associated key enzymes play central roles in the accumulation of lipid droplets in HCC. Enhanced cholesterol biosynthesis and attenuated bile acid biosynthesis play important roles in cholesterol accumulation in HCC. High levels of GSH and elevated Bcl2 and Ucp2 expression may contribute to a normal level of ROS in HCC.

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