SCD1 Expression is dispensable for hepatocarcinogenesis induced by AKT and Ras oncogenes in mice.

Abstract

Increased de novo lipogenesis is one of the major metabolic events in cancer. In human hepatocellular carcinoma (HCC), de novo lipogenesis has been found to be increased and associated with the activation of AKT/mTOR signaling. In mice, overexpression of an activated form of AKT results in increased lipogenesis and hepatic steatosis, ultimately leading to liver tumor development. Hepatocarcinogenesis is dramatically accelerated when AKT is co-expressed with an oncogenic form of N-Ras. SCD1, the major isoform of stearoyl-CoA desaturases, catalyzing the conversion of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA), is a key enzyme involved in de novo lipogenesis. While many studies demonstrated the requirement of SCD1 for tumor cell growth in vitro, whether SCD1 is necessary for tumor development in vivo has not been previously investigated. Here, we show that genetic ablation of SCD1 neither inhibits lipogenesis and hepatic steatosis in AKT-overexpressing mice nor affects liver tumor development in mice co-expressing AKT and Ras oncogenes. Molecular analysis showed that SCD2 was strongly upregulated in liver tumors from AKT/Ras injected SCD1(-/-) mice. Noticeably, concomitant silencing of SCD1 and SCD2 genes was highly detrimental for the growth of AKT/Ras cells in vitro. Altogether, our study provides the evidence, for the first time, that SCD1 expression is dispensable for AKT/mTOR-dependent hepatic steatosis and AKT/Ras-induced hepatocarcinogenesis in mice. Complete inhibition of stearoyl-CoA desaturase activity may be required to efficiently suppress liver tumor development.

• Authors: Lei Li, Chunmei Wang, Diego F Calvisi, Matthias Evert, Maria G Pilo, Lijie Jiang, Mariia Yuneva, Xin Chen
• Journal: PloS one (PLoS One) Vol. 8 Issue 9 Pg. e75104 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24069385 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Scd1 protein, mouse
• Stearoyl-CoA Desaturase
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics, metabolism)
• Disease Models, Animal
• Fatty Liver (genetics, metabolism, pathology)
• Female
• Gene Expression
• Genes, ras
• Lipid Metabolism
• Liver Neoplasms (genetics, metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Mice, Nude
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Stearoyl-CoA Desaturase (genetics, metabolism)