Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis
Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis
复制标题
DOI：
10.1158/0008-5472.can-06-3587
复制
发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Dietrich, Daniel R.
中科院分区：
文献类型：
--
作者：
Stemmer, Kerstin;Ellinger-Ziegelbauer, Heidrun;Dietrich, Daniel R.
Eker大鼠结节性硬化症2（Tsc 2）肿瘤抑制基因的显性生殖系突变杂合子被用作研究肾癌发生的模型。Eker和相应的野生型大鼠暴露于具有遗传毒性的马兜铃酸（AA）或非遗传毒性的赭曲霉毒素A（OTA），以阐明早期致癌物特异性基因表达的变化，并测试Eker大鼠是否对致癌物诱导的基因表达变化更敏感。雄性Eker和野生型大鼠每天用AA（10 mg/kg体重）或OTA（210 μ g/kg体重）管饲。在暴露1、3、7和14天后，分析肾组织病理学、肾小管细胞增殖和肾皮质/外髓质的AffyR基因表达谱。AA给药的Eker和野生型大鼠在所有评估变量中定性相当，表明Tsc 2独立的作用机制。OTA治疗导致轻微增加皮质病理和显着升高的细胞增殖在两个品系，虽然埃克大鼠更敏感。涉及磷脂酰肌醇3-激酶-AKT-Tsc 2-哺乳动物雷帕霉素信号传导靶点的基因失调，以及在肿瘤发生中突出的其他重要基因，与增强的细胞增殖和存在的癌前病变一起，表明Tsc 2参与OTA介导的毒性和致癌性，特别是因为涉及该途径的基因失调在Tsc 2突变体Eker大鼠中更为突出。
Eker rats heterozygous for a dominant germline mutation in the tuberous sclerosis 2 (Tsc2) tumor suppressor gene were used as a model to study renal carcinogenesis. Eker and corresponding wild-type rats were exposed to genotoxic aristolochic acid (AA) or non-genotoxic ochratoxin A (OTA) to elucidate early carcinogen-specific gene expression changes and to test whether Eker rats are more sensitive to carcinogen-induced changes in gene expression. Male Eker and wild-type rats were gavaged daily with AA (10 mg/kg body weight) or OTA (210 [mu g/kg body weight). After 1, 3, 7, and 14 days of exposure, renal histopathology, tubular cell proliferation, and Affymetrix gene expression profiles from renal cortex/outer medulla were analyzed. AA-treated Eker and wild-type rats were qualitatively comparable in all variables assessed, suggesting a Tsc2-independent mechanism of action. OTA treatment resulted in slightly increased cortical pathology and significantly elevated cell proliferation in both strains, although Eker rats were more sensitive. Deregulated genes involved in the phosphatidylinositol 3-kinase-AKT-Tsc2-mammalian target of rapamycin signaling, among other important genes prominent in tumorigenesis, in conjunction with the enhanced cell proliferation and presence of preneoplastic lesions suggested involvement of Tsc2 in OTA-mediated toxicity and carcinogenicity, especially as deregulation of genes involved in this pathway was more prominent in the Tsc2 mutant Eker rat.