Hydrogen peroxide-mediated nuclear factor kappaB activation in both liver and tumor cells during initial stages of hepatic metastasis.

Abstract

Various factors involved in tumor metastasis are regulated by the transcription factor nuclear factor kappaB (NF-kappaB). Because NF-kappaB activation may contribute to establishment of hepatic metastasis, its activation in liver cells and tumor cells was separately evaluated in a mouse model of hepatic metastasis. pNF-kappaB-Luc, a firefly luciferase-expressing plasmid DNA depending on the NF-kappaB activity, was injected into the tail vein of mice by the hydrodynamics-based procedure, a well-established method for gene transfer to BALB/c male mouse liver. The luciferase activity in the liver was significantly increased by an intraportal inoculation of murine adenocarcinoma colon26 cells, but not of peritoneal macrophages, suggesting that the NF-kappaB in liver cells is activated when tumor cells enter the hepatic circulation. Then, colon26 cells stably transfected with pNF-kappaB-Luc were inoculated. The firefly luciferase activity, an indicator of NF-kappaB activity in tumor cells, was significantly increased when colon26/NFkappaB-Luc cells were inoculated into the portal vein of BALB/c male mice. The NF-kappaB activation in both liver and tumor cells was significantly inhibited by injection of catalase derivatives, which have been reported to inhibit hepatic metastasis of tumor cells. These findings indicate for the first time that NF-kappaB, a key agent regulating the expression of various molecules involved in tumor metastasis, is activated in both liver and tumor cells during the initial stages of tumor metastasis through a hydrogen peroxide mediated pathway. Thus, the removal of hydrogen peroxide will be a promising approach to treating hepatic metastasis.