EPSIN 3, A Novel p53 Target, Regulates the Apoptotic Pathway and Gastric Carcinogenesis.
EPSIN 3, A Novel p53 Target, Regulates the Apoptotic Pathway and Gastric Carcinogenesis.
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DOI：
10.1016/j.neo.2016.12.010
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发表时间：
2017-03
期刊：
影响因子：
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通讯作者：
Matsuda K
中科院分区：
文献类型：
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作者：
Mori J;Tanikawa C;Ohnishi N;Funauchi Y;Toyoshima O;Ueda K;Matsuda K
背景与目的：细胞应激激活p53可诱导数百个靶基因的转录。为了阐明其下游通路的全图，我们筛选了阿霉素处理的HCT116 p53−/−或p53+/+细胞的cDNA微阵列数据集，并确定了EPSIN 3作为p53的新靶点。方法：采用报告基因法和CHIP法检测EPSIN 3基因座中p53的潜在结合序列。为了研究EPSIN 3在p53下游通路中的作用，我们评估了EPSIN 3敲低HCT116细胞或EPSIN 3缺陷小鼠DNA损伤诱导的凋亡。此外，我们还评估了EPSIN 3在胃腺癌、幽门螺杆菌感染或未感染的人胃黏膜、吲哚美辛诱导的小鼠急性胃炎组织中的表达水平。结果：在DNA损伤时，p53通过EPSIN 3启动子和第一内含子中的p53结合元件诱导EPSIN 3的表达。在体外和体内实验中，EPSIN 3的敲低导致了DNA损伤诱导的细胞凋亡的抵抗。EPSIN 3在胃癌组织中的表达较正常组织下调。此外，幽门螺杆菌感染和吲哚美辛诱导的急性胃炎可抑制胃黏膜EPSIN 3的表达。结论：EPSIN 3是p53的新靶点和凋亡的关键介质。慢性或急性粘膜炎症以及p53失活诱导EPSIN 3下调，随后引起细胞凋亡抵抗，这是癌细胞的一个标志。
BACKGROUND & AIM: p53 activation by cellular stresses induces the transcription of hundreds of its target genes. To elucidate the entire picture of its downstream pathway, we screened a cDNA microarray dataset of adriamycin-treated HCT116 p53−/− or p53+/+ cells and identified EPSIN 3 as a novel p53 target. METHODS: Potential p53 binding sequences in the EPSIN 3 locus were evaluated by reporter and CHIP assays. To investigate the role of EPSIN 3 in the p53 downstream pathway, we assessed DNA damage-induced apoptosis in EPSIN 3-knockdown HCT116 cells or Epsin 3-deficient mice. In addition, we evaluated EPSIN 3 expression levels in various tissues, including gastric adenocarcinoma, human gastric mucosa with or without Helicobacter pylori infection, and mouse acute gastritis tissues induced by indomethacin. RESULTS: In response to DNA damage, p53 induced the expression of EPSIN 3 through the p53 binding elements in the EPSIN 3 promoter and the first intron. Knockdown of EPSIN 3 resulted in resistance to DNA damage-induced apoptosis both in vitro and in vivo. EPSIN 3 expression was down-regulated in gastric cancer tissues compared with normal tissues. In addition, Helicobacter pylori infection and indomethacin-induced acute gastritis repressed EPSIN 3 expression in gastric mucosa. CONCLUSIONS: EPSIN 3 is a novel p53 target and a key mediator of apoptosis. Chronic or acute mucosal inflammation as well as p53 inactivation induced down-regulation of EPSIN 3 and subsequently caused apoptosis resistance, which is a hallmark of cancer cells.