Kuwata Kazunori, Inoue Kaoru, Ichimura Ryohei, Takahashi Miwa, Kodama Yukio, Shibutani Makoto, Yoshida Midori
1 Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
2 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.
Toxicol Pathol. 2017 Jun;45(4):493-505. doi: 10.1177/0192623317708898. Epub 2017 Jun 5.
We previously reported the contribution of constitutive androstane receptor (CAR) in cytotoxicity-related hepatocarcinogenesis induced by oxadiazon (OX) or acifluorfen (ACI), two pesticides categorized as protoporphyrinogen oxidase (PROTOX) inhibitors. The molecular characteristics of preneoplastic and neoplastic lesions induced by OX and ACI were immunohistochemically compared to those by phenobarbital (PB), a typical CAR activator, in wild-type (WT) and CAR knockout (CARKO) mice after diethylnitrosamine initiation. We focused on changes in β-catenin and its transcriptional product glutamine synthetase (GS). In PB-promoted foci and adenomas, nuclear accumulation of mutated β-catenin was increased with high frequency. PB treatment also increased the multiplicity and area of GS-positive foci and adenomas in WT mice. No foci and adenomas showed nuclear accumulation of β-catenin and expression of GS in CARKO mice, similar to both genotypes of mice treated with OX and ACI. Interestingly, hepatocellular carcinoma induced in ACI-treated WT mice showed nuclear accumulation of β-catenin and was positive for GS. Our results indicated that β-catenin mutations were not involved in early-stage hepatocarcinogenesis induced by PROTOX inhibitors in mice, although activation of β-catenin and CAR is important in PB-induced tumorigenesis. The significant differences in molecular profiles suggested involvements of multiple mode of actions for hepatocarcinogenesis induced by PROTOX inhibitors.
我们之前报道了组成型雄烷受体（CAR）在由恶草酮（OX）或三氟羧草醚（ACI）诱导的细胞毒性相关肝癌发生中的作用，OX和ACI这两种农药被归类为原卟啉原氧化酶（PROTOX）抑制剂。在二乙基亚硝胺启动后，对野生型（WT）和CAR基因敲除（CARKO）小鼠中，由OX和ACI诱导的癌前和肿瘤性病变的分子特征与典型的CAR激活剂苯巴比妥（PB）诱导的病变进行了免疫组织化学比较。我们重点关注了β-连环蛋白及其转录产物谷氨酰胺合成酶（GS）的变化。在PB促进的病灶和腺瘤中，突变型β-连环蛋白的核积累高频增加。PB处理还增加了WT小鼠中GS阳性病灶和腺瘤的数量及面积。在CARKO小鼠中，没有病灶和腺瘤显示β-连环蛋白的核积累及GS的表达，这与用OX和ACI处理的两种基因型小鼠相似。有趣的是，在ACI处理的WT小鼠中诱导的肝细胞癌显示β-连环蛋白的核积累且GS呈阳性。我们的结果表明，β-连环蛋白突变不参与小鼠中PROTOX抑制剂诱导的早期肝癌发生，尽管β-连环蛋白和CAR的激活在PB诱导的肿瘤发生中很重要。分子谱的显著差异表明PROTOX抑制剂诱导的肝癌发生涉及多种作用模式。
