IRTKS is correlated with progression and survival time of patients with gastric cancer
IRTKS is correlated with progression and survival time of patients with gastric cancer
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IRTKS与胃癌患者的进展和生存时间相关
DOI：
10.1136/gutjnl-2016-313478
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发表时间：
2018-08-01
期刊：
影响因子：
24.5
通讯作者：
Han, Ze-Guang
中科院分区：
文献类型：
--
作者：
Huang, Li-Yu;Wang, Xuefei;Han, Ze-Guang
背景与目的IRTKS作为一种新的抑癌基因P53的调节因子，其在胃癌发病机制中的作用尚不清楚。设计：采用免疫组织化学方法检测527例人胃癌标本中IRTKS的表达。我们建立了IRTKS缺陷小鼠和P53缺陷小鼠，以观察这些小鼠的存活时间，并分离小鼠胚胎成纤维细胞(MEF)以评估体内的致瘤性。免疫共沉淀法研究P53、MDM2和IRTKS之间的相互作用以及P53的泛素化。结果IRTKS在人胃癌组织中显著过表达，与野生型P53表达呈负相关。在野生型p53患者中，IRTKS高表达患者(n=141)的生存时间明显短于IRTK低表达患者(n=0.0153)。具有IRTKS缺陷的杂合子P53+/−小鼠的肿瘤发生显著延迟，无瘤生存时间延长。不含IRTK的P53+/−MEF体内致瘤性减弱。IRTKS缺失上调了p53及其靶基因bax和p21的表达。有趣的是，IRTKS的过表达促进了MEF和胃癌细胞中P53的泛素化和降解。在DNA损伤条件下，IRTKS在Ser331被激活的Chk2激酶磷酸化，然后与P53解离，以及P53特异性的E3泛素连接酶MDM2，导致P53泛素化和降解减弱。结论IRTKS过表达可能通过泛素/蛋白酶体途径促进P53蛋白降解，与野生型P53胃癌患者的病程和总生存期呈负相关。
Background and objectives IRTKS functions as a novel regulator of tumour suppressor p53; however, the role of IRTKS in pathogenesis of gastric cancer is unclear. Design We used immunohistochemistry to detect IRTKS levels in 527 human gastric cancer specimens. We generated both IRTKS-deficient and p53-deficient mice to observe survival time of these mice and to isolate mouse embryonic fibroblasts (MEFs) for evaluating in vivo tumorigenicity. Co-immunoprecipitation was used to study the interaction among p53, MDM2 and IRTKS, as well as the ubiquitination of p53. Results IRTKS was significantly overexpressed in human gastric cancer, which was conversely associated with wild-type p53 expression. Among patients with wild-type p53 (n=206), those with high IRTKS expression (n=141) had a shorter survival time than those with low IRTKS (n=65) (p=0.0153). Heterozygous p53 +/− mice with IRTKS deficiency exhibited significantly delayed tumorigenesis and an extended tumour-free survival time. p53+/− MEFs without IRTKS exhibited attenuated in vivo tumorigenicity. IRTKS depletion upregulated p53 and its target genes, such as BAX and p21. Intriguingly, IRTKS overexpression promoted p53 ubiquitination and degradation in MEFs and gastric cancer cells. Under DNA damage conditions, IRTKS was phosphorylated at Ser331 by the activated Chk2 kinase and then dissociated from p53, along with the p53-specific E3 ubiquitin ligase MDM2, resulting in attenuated p53 ubiquitination and degradation. Conclusion IRTKS overexpression is negatively correlated with progression and overall survival time of patients with gastric cancer with wild-type p53 through promotion of p53 degradation via the ubiquitin/proteasome pathway.