Mutoh Michihiro, Niho Naoko, Komiya Masami, Takahashi Mami, Ohtsubo Rina, Nakatogawa Kiyoshi, Ueda Kentaro, Sugimura Takashi, Wakabayashi Keiji
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Carcinogenesis. 2008 Apr;29(4):824-9. doi: 10.1093/carcin/bgn028. Epub 2008 Feb 6.
Obesity and hyperlipidemia are known to increase colorectal tumor risk. We noticed that Min mice, featuring a defect in the adenomatous polyposis coli (Apc) gene, develop intestinal polyps along with high serum triglyceride (TG) levels up to 10-fold those observed in wild-type mice. In these mice, messenger RNA (mRNA) expression of lipoprotein lipase, which catalyzes hydrolysis of TG, is downregulated. In the present study, we focused on adipocytokines, especially plasminogen activator inhibitor-1 (Pai-1), which is involved in hyperlipidemic status and may promote intestinal polyp formation in Min mice. Serum Pai-1 levels in the 15-week-old male Min mice were eight times higher than in wild-type mice and hepatic Pai-1 mRNA levels were 11-fold increased. In addition, Pai-1 immunostaining was strong in small intestinal epithelial cells of Min mice. Administration of a PAI-1 inhibitor, SK-216, at 25, 50 and 100 p.p.m. doses in the diet for 9 weeks reduced serum Pai-1 levels and hepatic Pai-1 mRNA levels of Min mice to the wild-type levels. Moreover, SK-216 at 50 and 100 p.p.m. significantly reduced total numbers of intestinal polyps to 64 and 56% of the untreated group value, respectively. Serum TG levels were also decreased by 43% at the dose of 100 p.p.m. Administration of 50 p.p.m. SK-116, another PAI-1 inhibitor, for 9 weeks similarly reduced serum Pai-1 levels and total numbers of intestinal polyps to 70% of the untreated group value. These results indicate that Pai-1 induction associated with hypertriglyceridemia may contribute to intestinal polyp formation with Apc deficiency, and PAI-1 could thus be a novel target for colorectal chemopreventive agents.
众所周知，肥胖和高脂血症会增加结直肠肿瘤风险。我们注意到，携带腺瘤性息肉病大肠杆菌（Apc）基因缺陷的Min小鼠会出现肠道息肉，同时血清甘油三酯（TG）水平高达野生型小鼠的10倍。在这些小鼠中，催化TG水解的脂蛋白脂肪酶的信使核糖核酸（mRNA）表达下调。在本研究中，我们关注脂肪细胞因子，尤其是纤溶酶原激活物抑制剂-1（Pai-1），它与高脂血症状态有关，可能会促进Min小鼠肠道息肉的形成。15周龄雄性Min小鼠的血清Pai-1水平比野生型小鼠高8倍，肝脏Pai-1 mRNA水平增加了11倍。此外，Min小鼠小肠上皮细胞中的Pai-1免疫染色很强。在饮食中以25、50和100 ppm的剂量给予PAI-1抑制剂SK-216，持续9周，可将Min小鼠的血清Pai-1水平和肝脏Pai-1 mRNA水平降低至野生型水平。此外，50和100 ppm的SK-216分别将肠道息肉总数显著降低至未治疗组数值的64%和56%。在100 ppm的剂量下，血清TG水平也降低了43%。给予另一种PAI-1抑制剂50 ppm的SK-116，持续9周，同样将血清Pai-1水平和肠道息肉总数降低至未治疗组数值的70%。这些结果表明，与高甘油三酯血症相关的Pai-1诱导可能导致Apc缺乏时的肠道息肉形成，因此PAI-1可能是结直肠癌化学预防药物的一个新靶点。
