Kobayashi Yuki, Nishikawa Makiya, Hyoudou Kenji, Yamashita Fumiyoshi, Hashida Mitsuru
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Cancer Sci. 2008 Aug;99(8):1546-52. doi: 10.1111/j.1349-7006.2008.00856.x.
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.
肿瘤转移涉及的多种因素受转录因子核因子κB（NF-κB）调控。由于NF-κB激活可能有助于肝转移的形成，因此在肝转移小鼠模型中分别评估了其在肝细胞和肿瘤细胞中的激活情况。通过基于流体动力学的方法（一种已确立的将基因导入BALB/c雄性小鼠肝脏的方法），将依赖于NF-κB活性的表达萤火虫荧光素酶的质粒DNA（pNF-κB-Luc）注入小鼠尾静脉。经门静脉接种鼠结肠腺癌colon26细胞可显著增加肝脏中的荧光素酶活性，但接种腹膜巨噬细胞则不会，这表明当肿瘤细胞进入肝循环时，肝细胞中的NF-κB被激活。然后，接种稳定转染pNF-κB-Luc的colon26细胞。当将colon26/NFκB-Luc细胞接种到BALB/c雄性小鼠的门静脉中时，作为肿瘤细胞中NF-κB活性指标的萤火虫荧光素酶活性显著增加。注射过氧化氢酶衍生物可显著抑制肝脏和肿瘤细胞中的NF-κB激活，据报道过氧化氢酶衍生物可抑制肿瘤细胞的肝转移。这些发现首次表明，作为调控肿瘤转移相关多种分子表达的关键因子，NF-κB在肿瘤转移初始阶段通过过氧化氢介导的途径在肝脏和肿瘤细胞中均被激活。因此，去除过氧化氢将是治疗肝转移的一种有前景的方法。
