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The Chemopreventive Role of Ursodeoxycholic Acid in Colon Cancer Model : Suppressive Effects on Enhanced Group II Phospholipase A2 Expression

熊去氧胆酸在结肠癌模型中的化学预防作用：对增强的 II 族磷脂酶 A2 表达的抑制作用

基本信息

批准号：
08670555
负责人：
MATSUZAKI Yasushi
金额：
$ 1.41万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

We here report the possible suppressive mechanisms of ursodeoxycholic acid (UDCA) on azoxymethane (AOM) -induced colon cancer model rat. In relation to arachidonate metabolism, we focused on the regulation of group II phospholipase A_2 (PLA_2) expression after AOM treatment. (Materials and Methods) (1) F344 rats were fed standard diet containing 0.4% or 1% of UDCA.Total aberrant crypt counts along with enzymatic activity, protein mass, and steady-state mRAN levels of group II PLA_2 were determined at 2,4,6,12 weeks after exposure of AOM.(2) HepG2 cells incubated with 50microM UDCA were stimulated by IL-6 and TNF-alpha. The expression levels of group II PLA_2 protein and mRNA were determined. (Results) (1) Twelve weeks after AOM exposure, the total number of aberrant crypt foci in 0.4% UDCA-diet fed rats and 1% UDCA-diet fed rats was significantly decreased compared to the untreated animals. The mucosal concentration of PGE_2 and 6-keto-PGF1alpha were significantly lower in the UDCA-trested rats than untreated rats. In correlation with lowering, the enhanced activity, protien mass, and mRNA levels of group II PLA_2 were significantly attenuated in the UDCA-treated animals. (2) Pro-inflammatory cytokine-induced group II PLA_2 expression in HepG2 cells were suppressed by incubation with UDCA.(Conclusions) UDCA administration decreased the total number of aberrant crypt foci in AOM-treated colonic tissue in which the enhanced group II PLA_2 expression was significantly attenuated. This chemopreventive role of UDCA in colon carcinogenesis may lie in its modulation of the arachidonate metabolism in colonic mucosa. In addition, it is supposed that this suppressive effect may be caused from direct action of UDCA to inflammed cells.

本文报道熊去氧胆酸（UDCA）对氧化偶氮甲烷（AOM）诱发大鼠结肠癌的抑制作用及其可能的机制。在花生四烯酸代谢方面，我们重点研究了AOM处理后Ⅱ型磷脂酶A_2（PLA_2）表达的调节。（材料与方法）（1）给F344大鼠喂饲含0.4%或1% UDCA的标准饲料，于AOM染毒后2、4、6、12周测定Ⅱ组PLA_2的异常隐窝总数沿着、酶活性、蛋白质质量和稳态mRAN水平。(2)用IL-6和TNF-α刺激与50 μ M UDCA孵育的HepG 2细胞。测定Ⅱ型PLA_2蛋白和mRNA的表达水平。（结果）（1）AOM暴露12周后，0.4%UDCA饲料喂养组和1%UDCA饲料喂养组大鼠的异常隐窝病灶总数明显低于未处理组。UDCA组大鼠胃粘膜PGE_2和6-keto-PGF_（1 α）含量明显低于对照组。UDCA处理组Ⅱ型PLA_2的活性、蛋白质量和mRNA水平均显著降低。(2)UDCA可抑制HepG 2细胞中促炎性丝氨酸诱导的Ⅱ型PLA_2表达。（结论）UDCA可减少AOM处理的结肠组织中异常隐窝病灶的总数，并可显著降低II组PLA_2的表达。UDCA在结肠癌发生中的化学预防作用可能在于其调节结肠粘膜中的花生四烯酸代谢。此外，推测这种抑制作用可能是由UDCA对炎症细胞的直接作用引起的。