Department of Obstetrics and Gynecology, Shanghai First People's Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
Cancer Lett. 2015 May 1;360(2):269-79. doi: 10.1016/j.canlet.2015.02.028. Epub 2015 Feb 16.
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 REGγ 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 REGγ expression, and chromatin immunoprecipitation coupled with PCR further indicated that p53-R248Q bound to the REGγ gene promoter at a p53 responsive element. Silencing of REGγ in EC cells attenuated the cell proliferation, migration and invasion abilities, whereas overexpression of p53-R248Q rescued these activities. Overexpression of REGγ also induced an epithelial-mesenchymal transition phenotype. Moreover, a mouse xenograft tumor model showed that REGγ promoted tumor growth, further demonstrating a p53-R248Q-REGγ oncogenic pathway. Finally, examination of EC and normal endometrium specimens confirmed the oncogenic role of REGγ, in that REGγ was more highly overexpressed in p53-positive specimens than in p53-negative specimens. Our data suggest that REGγ is a promising therapeutic target for EC with the p53-R248Q mutation.
p53 突变在子宫内膜癌（EC）的肿瘤发生中起着关键作用，在这里我们报告功能获得性突变 p53-R248Q 靶向蛋白酶体激活剂 REGγ 以促进 EC 的进展。p53 表达增加与 EC 标本中的高病理分级和淋巴结转移显著相关。在 EC 细胞中操纵 p53-R248Q 会导致 REGγ 表达的同时变化，染色质免疫沉淀结合 PCR 进一步表明 p53-R248Q 在 p53 反应元件处结合 REGγ 基因启动子。在 EC 细胞中沉默 REGγ 会减弱细胞增殖、迁移和侵袭能力，而过表达 p53-R248Q 则挽救了这些活性。过表达 REGγ 还诱导上皮-间充质转化表型。此外，小鼠异种移植肿瘤模型表明 REGγ 促进肿瘤生长，进一步证明了 p53-R248Q-REGγ 致癌途径。最后，对 EC 和正常子宫内膜标本的检查证实了 REGγ 的致癌作用，即在 p53 阳性标本中 REGγ 的表达高于 p53 阴性标本。我们的数据表明，REGγ 是具有 p53-R248Q 突变的 EC 的有前途的治疗靶点。
