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 (PUFA) dampen inflammation in the liver and decrease formation of 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 to wild-type (wt) littermates. Plasma TNF-α levels and liver COX-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 diethylnitrosamine.

In vitro experiments showed that 18-HEPE and 17-HDHA could effectively suppress LPS-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, likely through inhibiting liver inflammation.

The findings also point to a potential anti-cancer role for the n-3 PUFA-derived lipid mediators 18-HEPE and 17-HDHA, which can down-regulate the important pro-inflammatory and pro-proliferative factor TNF-αα.