Abstract：
Ochratoxin A (OTA), as one of the most important and harmful mycotoxins, is classed as possible human carcinogen (group 2B). As we all know, DNA damage may cause genomic instability, cell cycle disorder, activation of DNA damage pathway, and stimulation of DNA repair system. To explore the roles of DNA damage repair protein (hMLH1) on OTA-induced G2 arrest, the DNA damage, chromosome aberration, cell cycle distribution and p53-p21 signaling pathway were evaluatd after different time OTA exposure (6, 12, 24, 48h) in immortalized human gastric epithelial cells (GES-1). Our results demonstrated that OTA exposure could trigger genomic instability, DNA damage and G2 phase arrest of GES-1 cells. At the same time, OTA treatment could increase the expression of hMLH1, and induce phosphorylation of the p53 protein, as well as p21, in response to DNA damage. Finally, inhibition of hMLH1 by siRNA effectively prevented the activation of p53-p21 signaling pathway and rescued the G2 arrest elicited by OTA. This study demonstrated that hMLH1-p53-p21 signaling pathway played an important role in DNA damage and G2 cell cycle arrest the mediated by OTA in GES-1 cells.
摘要：
曲霉毒素A(OTA),作为最重要和最有害的真菌毒素之一，被归类为可能的人类致癌物（2B组）。我们都知道,DNA损伤可能导致基因组不稳定,细胞周期紊乱，激活DNA损伤途径，和刺激DNA修复系统。探讨DNA损伤修复蛋白(hMLH1)在OTA诱导G2阻滞中的作用,DNA损伤,染色体畸变,在永生化人胃上皮细胞（GES-1）中不同时间（6、12、24、48h）暴露OTA后，评估细胞周期分布和p53-p21信号通路。我们的结果表明，OTA暴露可能引发基因组不稳定，GES-1细胞的DNA损伤和G2期阻滞。同时,OTA处理可以增加hMLH1的表达，并诱导p53蛋白的磷酸化，以及p21，对DNA损伤的反应。最后,siRNA对hMLH1的抑制作用有效地阻止了p53-p21信号通路的激活，并挽救了OTA引起的G2阻滞。本研究表明hMLH1-p53-p21信号通路在OTA介导的GES-1细胞DNA损伤和G2细胞周期阻滞中起重要作用。
