The G(2) phase arrest induced by sterigmatocystin is dependent on hMLH1-ERK/p38-p53 pathway in human esophageal epithelium cells in vitro
The G(2) phase arrest induced by sterigmatocystin is dependent on hMLH1-ERK/p38-p53 pathway in human esophageal epithelium cells in vitro
复制标题
体外人食管上皮细胞中杂色曲霉素诱导的 G(2) 期阻滞依赖于 hMLH1-ERK/p38-p53 通路
DOI：
10.1016/j.fct.2018.03.012
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发表时间：
2018
影响因子：
4.3
通讯作者：
Zhang Xianghong
中科院分区：
文献类型：
--
作者：
Cui Jinfeng;Wang Juan;Huang Shujuan;Jiang Xiujuan;Li Yuehong;Wu Wenxin;Zhang Xianghong
杂色曲霉素（ST）是黄曲霉毒素的前体物质，属于2B类致癌物质。本课题组前期研究发现，ST诱导的人食管鳞状上皮细胞系HET-1A细胞G2期阻滞与错配修复（MMR）通路和p53信号通路有关。研究表明，ERK、JNK和p38信号通路在其他几种致癌物诱导的细胞周期阻滞中起重要作用。然而，MAPK通路在ST诱导的G2期阻滞中的作用以及MMR和p53信号通路之间的联系尚不清楚。本研究首次探讨了丝裂原活化蛋白激酶（MAPK）信号通路在ST诱导G2期阻滞中的作用，发现ST通过MAPK信号通路（ERK和p38通路，而非JNK通路）上调G2/M期调控因子的表达。通过沉默hMLH 1表达阻断MMR通路可抑制ST引起的ERK、p38和p53的激活，进而减弱ST引起的G2期阻滞。总之，本研究表明，在ST诱导的DNA损伤反应中，hMLH 1首先被激活，然后触发ERK，HET-1A细胞中p38和p53的激活最终导致G2期阻滞。
Sterigmatocystin (ST), being a precursor of aflatoxin, is categorized as Group 2B carcinogen. Our previous studies found that both mismatch repair (MMR) pathways and p53 signaling pathway were involved in ST-induced G2cell cycle arrest in human esophageal squamous epithelial cell line, HET-1A,in vitro. Studies showed that ERK, JNK and p38 signaling pathways played important roles in cell cycle arrest induced by several other carcinogens. However, the role of MAPK pathway and the links between the MMR and p53 signaling pathways in ST induced G2phase arrest is still not clarified. In the present study, we first explored the role of MAPK pathway upon ST induced G2arrest, and found that ST up-regulated the expression of G2/M regulatory factors through MAPK signaling pathway (both ERK and p38, but not JNK pathway). The inhibition of ERK and p38 significantly inhibited p53 activation by ST. Blockage of MMR pathway by silencing hMLH1 expression inhibited ERK, p38 and p53 activation and then attenuated G2arrest by ST. Thus, in conclusion, the current study demonstrated that in response to ST induced DNA damage, hMLH1 was first activated, then triggered ERK, p38 and p53 activation and finally resulted in G2arrest in HET-1A cells.