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.
Highlights
Hepatocellular carcinoma (HCC) is a heterogeneous cancer with no promising treatments
To investigate the common metabolomics and transcriptomics related to hepatocellular carcinoma (HCC) induced by the ras oncogene, Ras-Tg and wild-type males were sacrificed at 9 months of age, and the hepatic tumors and wild-type liver tissues were sampled
The liver is the major organ for regulating lipid metabolism, and changes in lipid homeostasis are observed in various liver diseases [26]
Summary
Hepatocellular carcinoma (HCC) is a heterogeneous cancer with no promising treatments. Murine HCCs express H-ras, Bioinformatic Analysis of Hras12V-Induced HCC which is activated in 70% of cases This evidence supports the view that the Ras pathway plays crucial roles in hepatocarcinogenesis [5]. Phenotypes of hepatic adenoma are similar to altered foci but with a larger size (typically 2–5 mm) and are relatively well circumscribed; HCCs are large in size (typically >5 mm), have a trabecular arrangement of tumor cells, and have highly anaplastic cells with evidence of necrosis [5]. These hepatic alterations are in dominant PCNA-positive cells with abundant droplets but have rare apoptotic signs [5]. We and other researchers found that B lymphocytes, FoxM1, and miR-221 play crucial roles in HCC by using Ras-Tg mice [7, 9, 12]
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