Adler Melanie, Müller Katja, Rached Eva, Dekant Wolfgang, Mally Angela
Department of Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
Carcinogenesis. 2009 Apr;30(4):711-9. doi: 10.1093/carcin/bgp049. Epub 2009 Feb 23.
Ochratoxin A (OTA) is a potent renal carcinogen, but little is known regarding the mechanism of OTA carcinogenicity. Early histopathological alterations induced by OTA in rat kidney include single cell death, stimulation of cell proliferation and prominent karyomegaly indicative of blocked nuclear division during mitosis. Based on these observations, it has been suggested that disruption of mitosis by OTA may be the principal cause of cell death and subsequent trigger for cell proliferation to compensate for cell loss. To gain further insight into the molecular mechanism of OTA toxicity, we used targeted quantitative real-time polymerase chain reaction arrays to investigate the expression of genes involved in cell cycle control and mitosis in kidneys of male F344 rats treated with 0, 21, 70 and 210 microg/kg body wt OTA for up to 90 days. Treatment with OTA resulted in overexpression of key regulators of mitosis, including the mitotic protein kinases Polo-like kinase 1, Aurora B and cyclin-dependent kinase 1 (Cdk1Cdc2), several cyclins and cyclin-dependent kinase inhibitors, topoisomerase II and survivin. Immunohistochemical analysis confirmed upregulation of Cdk1, p21(WAF1/CIP1), topoisomerase II and survivin in S3 proximal tubule cells, from which OTA-induced tumors in rats arise, and demonstrated increased phosphorylation of histone H3, a target of Aurora B. Importantly, many of the genes found to be deregulated in response to OTA have been linked to chromosomal instability and malignant transformation, supporting the hypothesis that aberrant mitosis, resulting in blocked or asymmetric cell division, accompanied by an increased risk of aneuploidy acquisition, may play a critical role in OTA carcinogenicity.
赭曲霉毒素A（OTA）是一种强效肾致癌物，但关于OTA致癌性的机制却知之甚少。OTA在大鼠肾脏中诱导的早期组织病理学改变包括单细胞死亡、细胞增殖刺激以及有丝分裂期间核分裂受阻所指示的显著核肿大。基于这些观察结果，有人提出OTA对有丝分裂的破坏可能是细胞死亡的主要原因，也是随后细胞增殖以补偿细胞损失的触发因素。为了进一步深入了解OTA毒性的分子机制，我们使用靶向定量实时聚合酶链反应阵列，研究了雄性F344大鼠肾脏中参与细胞周期控制和有丝分裂的基因的表达，这些大鼠分别接受0、21、70和210微克/千克体重的OTA处理，最长达90天。OTA处理导致有丝分裂关键调节因子的过表达，包括有丝分裂蛋白激酶Polo样激酶1、极光激酶B和细胞周期蛋白依赖性激酶1（Cdk1/Cdc2）、几种细胞周期蛋白和细胞周期蛋白依赖性激酶抑制剂、拓扑异构酶II和生存素。免疫组织化学分析证实，在大鼠OTA诱导肿瘤起源的S3近端小管细胞中，Cdk1、p21（WAF1/CIP1）、拓扑异构酶II和生存素上调，并证明了极光激酶B的靶标组蛋白H3的磷酸化增加。重要的是，许多因OTA而失调的基因与染色体不稳定性和恶性转化有关，这支持了以下假设：异常有丝分裂导致细胞分裂受阻或不对称，同时非整倍体获得风险增加，可能在OTA致癌性中起关键作用。
