Suppression of AhR signaling pathway is associated with the down-regulation of UDP-glucuronosyltransferases during BBN-induced urinary bladder carcinogenesis in mice
Suppression of AhR signaling pathway is associated with the down-regulation of UDP-glucuronosyltransferases during BBN-induced urinary bladder carcinogenesis in mice
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DOI：
10.1093/jb/mvp169
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发表时间：
2010-03-01
影响因子：
2.7
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Iida, Katsuyuki;Mimura, Junsei;Yamamoto, Masayuki
致癌物解毒酶的下调可能是通过增加靶器官中的致癌物浓度而形成肿瘤的关键因素。先前的报告显示，UGT 1A mRNA的表达在某些人类癌症组织中丢失或减少，包括膀胱癌。为了阐明这种下调机制，我们使用了N-亚硝基丁基（4-羟丁基）胺（BBN）诱导的小鼠膀胱致癌模型。与人类癌症相似，BBN诱导的膀胱癌中Ugt 1a 6、Ugt 1a 9和总Ugt 1a mRNA的表达与正常小鼠相比明显降低。BBN以时间依赖性方式下调基础Ugt 1a mRNA表达，并且在BBN处理的前2周内是可逆的。然而，在BBN治疗4周后，停止BBN治疗后，抑制变得持续。芳烃受体（Aryl hydrocarbon receptor，AhR）调节Ugt 1a mRNA的组成型和诱导型表达。我们发现，组成型Ugt 1a mRNA表达减少AhR敲除（KO）小鼠膀胱。此外，BBN诱导的Ugt 1a下调在AhR KO小鼠中丢失，并且典型的AhR靶基因Cyp 1a 1在膀胱中被BBN类似地下调。这些结果表明，在BBN诱导的癌变过程中，BBN通过抑制AhR信号通路抑制Ugt 1a mRNA的表达。
Down-regulation of carcinogen detoxifying enzymes might be a critical factor in tumour formation by increasing the carcinogen concentration in the target organ. Previous reports revealed that the expression of UGT1A mRNA is either lost or decreased in certain human cancer tissues, including urinary bladder cancer. To elucidate this down-regulation mechanism, we used an N-nitrosobutyl (4-hydroxybutyl) amine (BBN)-induced mouse urinary bladder carcinogenesis model. Similar to human cancer, the expressions of Ugt1a6, Ugt1a9 and total Ugt1a mRNA in the BBN-induced bladder cancer were markedly decreased compared with those of normal mice. BBN down-regulated the basal Ugt1a mRNA expression in a time-dependent manner and this was reversible in the first 2 weeks of BBN treatment. However, after 4 weeks of BBN treatment the repression became persistent after the cessation of BBN treatment. Aryl hydrocarbon receptor (AhR) regulates the constitutive and inducible expression of Ugt1a mRNA. We found that the constitutive Ugt1a mRNA expression is decreased in the bladder of AhR knockout (KO) mice. Furthermore, BBN-induced Ugt1a down-regulation was lost in AhR KO mice, and the canonical AhR target gene Cyp1a1 was similarly down-regulated by BBN in the bladder. These results demonstrate that BBN repressed Ugt1a mRNA expression via suppression of AhR signaling pathway during BBN-induced carcinogenesis.