title: Estrogen stimulates the proliferation of human endometrial cancer cells by stabilizing nucleophosmin/B23 (NPM/B23).
abstract: Unopposed estrogen exposure is an important factor in the tumorigenesis of endometrial cancer. Nucleophosmin/B23 (NPM/B23), a phosphoprotein that has pleiotropic functions in cells, plays an important role in various cancers. However, the regulatory role of NPM/B23 in estrogen signaling in endometrial cancer has not been explored. Here, we report that NPM/B23 was required for estrogen-induced endometrial proliferation, and the increase in NPM/B23 was estrogen receptor α-dependent. Furthermore, estrogen increased NPM/B23 protein levels by repressing its ubiquitination and subsequently stabilizing the protein. The overexpression of the alternate reading frame (ARF) suppressed the estrogen-induced increase in the NPM/B23 protein levels, indicating that ARF inhibited the observed estrogen-mediated NPM/B23 stabilization. Our results suggest that one of the effects of estrogen on endometrial proliferation is the suppression of the NPM/B23-ARF interaction and the subsequent increase in NPM/B23 protein levels. This novel characterization of NPM/B23 in estrogen-mediated cell proliferation may extend our understanding of the tumorigenesis of steroid hormone-related cancers.
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Linkou Medical Center, 5 Fushin Street, Guishan, Taoyuan, 333, Taiwan. angel945@cgmh.org.tw
authors.forename: Angel
authors.initials: A
authors.lastname: Chao
authors.forename: Chiao-Yun
authors.initials: CY
authors.lastname: Lin
authors.forename: Chia-Lung
authors.initials: CL
authors.lastname: Tsai
authors.forename: Swei
authors.initials: S
authors.lastname: Hsueh
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Lin
authors.forename: Cheng-Tao
authors.initials: CT
authors.lastname: Lin
authors.forename: Hung-Hsueh
authors.initials: HH
authors.lastname: Chou
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Wang
authors.forename: Chyong-Huey
authors.initials: CH
authors.lastname: Lai
authors.forename: Hsin-Shih
authors.initials: HS
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016889:Endometrial Neoplasms / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D034741:RNA, Small Interfering / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D025803:Tumor Suppressor Protein p14ARF; D000090243:Nucleophosmin; D004958:Estradiol