Suppressed liver tumorigenesis in fat-1 mice with elevated omega-3 fatty acids is associated with increased omega-3 derived lipid mediators and reduced TNF-α

• Published in: Carcinogenesis (New York) 2011-06, Vol.32 (6), p.897-903
• Main Authors: WEYLANDT, Karsten H, KRAUSE, Lena F, GOMOLKA, Beate, CHIU, Cheng-Ying, BILAL, Siileyman, NADOLNY, Anja, WAECHTER, Simon F, FISCHER, Andreas, ROTHE, Michael, KANG, Jing X
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Caenorhabditis elegans; Caenorhabditis elegans Proteins - physiology; Cancer Prevention; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - prevention & control; Cells, Cultured; Chemical agents; Chromatography, Gas; Docosahexaenoic Acids - metabolism; Fatty Acid Desaturases - physiology; Fatty Acids, Omega-3 - metabolism; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - prevention & control; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Medical sciences; Mice; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgr049

Liver tumors, particularly hepatocellular carcinoma (HCC), are a major cause of morbidity and mortality worldwide. The development of HCC is mostly associated with chronic inflammatory liver disease of various etiologies. Previous studies have shown that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) dampen inflammation in the liver and decrease formation of tumor necrosis factor (TNF)-α. In this study, we used the fat-1 transgenic mouse model, which endogenously forms n-3 PUFA from n-6 PUFA to determine the effect of an increased n-3 PUFA tissue status on tumor formation in the diethylnitrosamine (DEN)-induced liver tumor model. Our results showed a decrease in tumor formation, in terms of size and number, in fat-1 mice compared with wild-type littermates. Plasma TNF-α levels and liver cyclooxygenase-2 expression were markedly lower in fat-1 mice. Furthermore, there was a decreased fibrotic activity in the livers of fat-1 mice. Lipidomics analyses of lipid mediators revealed significantly increased levels of the n-3 PUFA-derived 18-hydroxyeicosapentaenoic acid (18-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDHA) in the livers of fat-1 animals treated with DEN. In vitro experiments showed that 18-HEPE and 17-HDHA could effectively suppress lipopolysacharide-triggered TNF-α formation in a murine macrophage cell line. The results of this study provide evidence that an increased tissue status of n-3 PUFA suppresses liver tumorigenesis, probably through inhibiting liver inflammation. The findings also point to a potential anticancer role for the n-3 PUFA-derived lipid mediators 18-HEPE and 17-HDHA, which can downregulate the important proinflammatory and proproliferative factor TNF-α.