Fat-1 Gene Inhibit Hepatocarcinogenesis Induced by AKT and Ras Oncogenes in Mice

Background and Aim: n-3 PUFAs have been shown to have multiple biological effects on cancers. The fat-1 gene encodes an n-3 desaturase that introduces a double bond at the n-3 position of the hydrocarbon chain in n-6 fatty acids to form an n-3 fatty acid. Here we investigated the anti-tumorigenesis effect of Fat-1 gene. Methods : Mounting evidence indicates that activation of AKT and Ras pathways is a key oncogenic event in human hepatocarcinogenesis. Our previous results demonstrate that co-expression of AKT and N-Ras in the mouse liver promotes rapid hepatocarcinogenesis in vivo. Here we utilized hydrodynamic tail vein injection of Fat-1 gene to AKT/Ras hepatocarcinogenesis' model to testify its anti-tumorigenesis effect. Results : Hydrodynamic injection of Fat-1 gene could inhibit lipogenesis and affects liver tumor development in co-expressing AKT and Ras oncogenes' mice. Molecular analysis showed that Fat-1 gene strongly inhibited the Ras/MAPK and Akt/ mTORC cell signal pathway, and significantly inhibited de novo lipogenesis by inhibition of fatty acid biosynthesis gene (FASN, ACLY) and transcription factors (LXR-β, SREBP1), which were highly elevated in AKT/Ras mice. The AKT/Ras cells lines in vitro also showed the similar results. Noticeably, although the hydrodynamic injection of fat-1 gene showed significant inhibition effect of hepatocarcinogenesis, it didn't change fatty acid profile in various tissues of mice, which is different from previous studies by using Fat-1 transgenic mice. Conclusions Local expression of Fat-1 gene can achieve sufficient suppression of AKT/Ras-induced hepatocarcinogenesis. Thus, with multiple biological effects on various signal pathways, Fat-1 gene can prevent of hepatocarcinogenesis.