Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis

Antithrombin (AT) is not only a major regulator of hemostasis, but it shows anti-inflammatory properties as well. We aimed to investigate whether AT-insufficient mice increase susceptibility to liver tumorigenesis.

We induced the development of liver tumor in AT-insufficient (AT^+/-) mice and wild-type (AT^+/+) mice by treating them with diethylnitrosamine (DEN) and CCl₄. The development of liver tumors and liver inflammation were compared between these mouse groups. Following this, AT was administered to the AT-insufficient mice treated with DEN and CCl₄.

Tumor size and the number of DEN and CCl₄-induced liver tumors significantly increased in AT-insufficient mice compared with the wild-type mice. Serum transaminase levels, cell death, and the expression of cleaved caspase-3 in liver were increased in AT^+/-. Furthermore, hepatic neutrophil infiltrations and serum interleukin 6 and tumor necrosis factor-α levels were significantly elevated in AT-insufficient mice. The levels of 8-OHdG, oxidative DNA damage marker, in liver were significantly increased in AT-insufficient mice. Administration of AT led to a significant decrease in DEN- and CCl₄-induced liver injury and inflammation in AT-insufficient mice, compared with the wild-type group.

AT insufficiency led to increased susceptibility to liver tumorigenesis by increasing hepatic inflammation.