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J Mol Med (2013) 91:249259 DOI 10.1007/s00109-012-0950-8
ORIGINAL ARTICLE
Estrogen stimulates the proliferation of human endometrial cancer cells by stabilizing nucleophosmin/B23 (NPM/B23)
Angel Chao & Chiao-Yun Lin & Chia-Lung Tsai &
Swei Hsueh & Ying-Yu Lin & Cheng-Tao Lin &
Hung-Hsueh Chou & Tzu-Hao Wang &
Chyong-Huey Lai & Hsin-Shih Wang
Received: 2 May 2012 /Revised: 6 August 2012 /Accepted: 16 August 2012 /Published online: 29 August 2012 # Springer-Verlag 2012
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 -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/B23ARF 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 tumor-igenesis of steroid hormone-related cancers.
Keywords Estrogen . NPM/B23 . ER . ARF
Introduction
Endometrial cancer is the most common cancer of the female genital tract and accounts for nearly 50,000 deaths worldwide each year [1]. In Taiwan, the endometrial cancer incidence rank increased from 33 to 15 between 1991 and 2009 [2]. Unopposed estrogen effects are a risk factor for endometrial cancer [3], as estrogen mediates the proliferative responses of endometrial development. Upon estrogen binding, conformational changes lead to the dimerization of estrogen receptor (ER), followed by its binding to the promoter sites of target genes, where the recruitment of coactivators and/or corepressors lead to the regulation of gene expression [4].
Nucleophosmin/B23 (NPM/B23) is an abundant and ubiquitously expressed nucleolar phosphoprotein that is indispensable for various cellular processes including ribo-some biogenesis, centrosome duplication, cell cycle progression, apoptosis, and cell differentiation [58]. These NPM/B23 activities may be related to its role in...