title: Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGγ.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Bao
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Feizhou
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Che
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Tong
authors.affiliation: Center Laboratory of Shanghai First People's Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Chenyun
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital affiliated with Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Binya
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: wanxp@sjtu.edu.cn.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics*; D018269:Carcinoma, Endometrioid / Q000201:enzymology / Q000235:genetics*; D048708:Cell Growth Processes / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D016612:Paraffin Embedding; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D001324:Autoantigens; C099558:Ki antigen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D046988:Proteasome Endopeptidase Complex
keywords: EC; EMT; Invasion; Mutant p53; Proliferation; REGγ