Journal article
NEDD4 ubiquitin ligase is a putative oncogene in endometrial cancer that activates IGF-1R/PI3K/Akt signaling
Gynecologic Oncology, Vol.139(1), pp.127-133
10/2015
DOI: 10.1016/j.ygyno.2015.07.098
PMCID: PMC4586405
PMID: 26193427
Abstract
The PI3K/Akt pathway is frequently dysregulated in endometrial cancer, the most common gynecologic malignancy. Emerging evidence identifies the ubiquitin ligase NEDD4 as a key regulator of the PI3K/Akt pathway via activation of insulin-like growth factor-1 receptor (IGF-1R). Our objective was to understand the role of NEDD4 in endometrial cancer. NEDD4 expression was assessed by immunohistochemistry in a tissue microarray with 77 endometrial lesions ranging from normal benign endometrium to tumor specimens of varying stage and grade. Studies were extended to a panel of eight endometrial cancer cell lines phenotypically representing the most common endometrial patient tumors. Immunohistochemistry demonstrated robust staining of NEDD4 in endometrial tumor specimens, with greater NEDD4 expression in the most aggressive tumors. Expression of NEDD4 was detected in a majority of endometrial cancer cell lines surveyed. Exogenous overexpression of murine Nedd4 in endometrial cancer cell lines with modest endogenous NEDD4 expression resulted in a significant increase in the rate of proliferation. Nedd4 overexpression also promoted an increase in cell surface localization of IGF-1R and activation of Akt. Inhibition of PI3K/Akt signaling reversed the enhanced cell growth in Nedd4-overexpressing endometrial cancer cells. In addition, the expression of NEDD4 in endometrial tumors positively correlated with the Akt downstream effector FoxM1. This study identifies NEDD4 as a putative oncogene in endometrial cancer that may augment activation of the IGF-1R/PI3K/Akt signaling pathway. •NEDD4 is overexpressed in malignant compared to benign endometrium.•NEDD4 expression in endometrial tumors positively correlates with the levels of the oncogenic transcription factor FoxM1.•Overexpression of NEDD4 in endometrial cancer cells promotes IGF-1R cell surface localization, Akt activation and cell growth.
Details
- Title: Subtitle
- NEDD4 ubiquitin ligase is a putative oncogene in endometrial cancer that activates IGF-1R/PI3K/Akt signaling
- Creators
- Yuping Zhang - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USARenee Goodfellow - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USAYujun Li - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USAShujie Yang - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USAChristopher J Winters - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USAKristina W Thiel - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USAKimberly K Leslie - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USABaoli Yang - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Gynecologic Oncology, Vol.139(1), pp.127-133
- DOI
- 10.1016/j.ygyno.2015.07.098
- PMID
- 26193427
- PMCID
- PMC4586405
- NLM abbreviation
- Gynecol Oncol
- ISSN
- 0090-8258
- eISSN
- 1095-6859
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: NIH, award: R01CA99908, R01CA184101; name: American Cancer Society Institutional Research Grant; name: Department of Obstetrics and Gynecology Research Development Fund
- Language
- English
- Date published
- 10/2015
- Academic Unit
- Pathology; BioVentures Center; Obstetrics and Gynecology; Otolaryngology
- Record Identifier
- 9983931019602771
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