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

我们在此报道熊去氧胆酸（UDCA）对偶氮氧甲烷（AOM）诱导的结肠癌模型大鼠可能的抑制机制。在花生四烯酸代谢方面，我们重点研究了AOM对II组磷脂酶A_2 （PLA_2）表达的调节。（材料与方法）(1)分别饲喂含0.4%或1% UDCA的标准日粮。在AOM暴露后2、4、6、12周，测定II组PLA_2的总异常隐窝计数、酶活性、蛋白质量和稳态mRAN水平。(2)用50microM UDCA孵育HepG2细胞，IL-6和tnf - α刺激HepG2细胞。测定ⅱ组PLA_2蛋白及mRNA的表达水平。（结果）(1)AOM暴露12周后，0.4% udca日粮喂养大鼠和1% udca日粮喂养大鼠的异常隐窝灶总数较未处理大鼠显著减少。udca组大鼠粘膜PGE_2和6-酮- pgf1 α浓度明显低于未处理组大鼠。在udca处理的动物中，II组PLA_2的活性、蛋白质质量和mRNA水平的增强与降低相关，显著减弱。(2) UDCA孵育可抑制促炎细胞因子诱导的HepG2细胞II组PLA_2的表达。（结论）UDCA减少了aom处理的结肠组织中异常隐窝灶的总数，而增强的II组PLA_2表达明显减弱。UDCA在结肠癌发生中的化学预防作用可能在于其调节结肠黏膜的花生四烯酸代谢。另外，这种抑制作用可能是UDCA直接作用于炎症细胞所致。

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.