Yuping Zhang1, Renee Goodfellow2, Yujun Li3, Shujie Yang4, Christopher J Winters5, Kristina W Thiel6, Kimberly K Leslie7, Baoli Yang8. 1. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Yuping-zhang@uiowa.edu. 2. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: renee-goodfellow@uiowa.edu. 3. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Yujun-li@uiowa.edu. 4. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Shujie-yang@uiowa.edu. 5. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Christopher-winters@uiowa.edu. 6. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Kristina-thiel@uiowa.edu. 7. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Kimberly-leslie@uiowa.edu. 8. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Baoli-yang@uiowa.edu.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: This study identifies NEDD4 as a putative oncogene in endometrial cancer that may augment activation of the IGF-1R/PI3K/Akt signaling pathway.
OBJECTIVE: 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. METHODS: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 patienttumors. RESULTS: 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 murineNedd4 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. CONCLUSIONS: This study identifies NEDD4 as a putative oncogene in endometrial cancer that may augment activation of the IGF-1R/PI3K/Akt signaling pathway.
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