Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGγ
Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGγ
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突变体 p53 (p53-R248Q) 作为癌基因，通过上调 REGgamma 促进子宫内膜癌。
DOI：
10.1016/j.canlet.2015.02.028
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发表时间：
2015-05-01
期刊：
影响因子：
9.7
通讯作者：
Wan, Xiaoping
中科院分区：
文献类型：
--
作者：
Wang, Huihui;Bao, Wei;Wan, Xiaoping
P53突变在子宫内膜癌（EC）的肿瘤发生中起着关键作用，在此我们报道功能获得突变体p53-R248Q靶向蛋白酶体激活剂REG gamma以促进EC进展。 EC标本中p53表达增加与高病理分级和淋巴结转移显着相关。在 EC 细胞中操作 p53-R248Q 引起 REG gamma 表达的一致变化，染色质免疫沉淀与 PCR 结合进一步表明 p53-R248Q 在 p53 响应元件处与 REG gamma 基因启动子结合。 EC细胞中REG gamma的沉默减弱了细胞增殖、迁移和侵袭能力，而p53-R248Q的过度表达则挽救了这些活性。 REG γ 的过度表达也诱导上皮间质转化表型。此外，小鼠异种移植肿瘤模型显示 REG gamma 促进肿瘤生长，进一步证明了 p53-R248Q REG gamma 致癌途径。最后，对 EC 和正常子宫内膜标本的检查证实了 REG γ 的致癌作用，因为 REG γ 在 p53 阳性标本中比在 p53 阴性标本中过度表达。我们的数据表明 REG gamma 是 p53-R248Q 突变 EC 的一个有前途的治疗靶点。 (C) 2015 Elsevier Ireland Ltd. 保留所有权利。
P53 mutation plays a pivotal role in tumorigenesis of endometrial cancer (EC), here we report that the gain-of-function mutant p53-R248Q targets the proteasome activator REG gamma to promote EC progression. Increased p53 expression significantly correlated with high pathological grade and lymph node metastasis in EC specimens. Manipulation of p53-R248Q in EC cells caused coincident changes in REG gamma expression, and chromatin immunoprecipitation coupled with PCR further indicated that p53-R248Q bound to the REG gamma gene promoter at a p53 responsive element. Silencing of REG gamma in EC cells attenuated the cell proliferation, migration and invasion abilities, whereas overexpression of p53-R248Q rescued these activities. Overexpression of REG gamma also induced an epithelial mesenchymal transition phenotype. Moreover, a mouse xenograft tumor model showed that REG gamma promoted tumor growth, further demonstrating a p53-R248Q REG gamma oncogenic pathway. Finally, examination of EC and normal endometrium specimens confirmed the oncogenic role of REG gamma, in that REG gamma was more highly overexpressed in p53-positive specimens than in p53-negative specimens. Our data suggest that REG gamma is a promising therapeutic target for EC with the p53-R248Q mutation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.