title: NEDD4 ubiquitin ligase is a putative oncogene in endometrial cancer that activates IGF-1R/PI3K/Akt signaling.
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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Yuping-zhang@uiowa.edu.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: renee-goodfellow@uiowa.edu.
authors.forename: Renee
authors.initials: R
authors.lastname: Goodfellow
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Yujun-li@uiowa.edu.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Shujie
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Christopher-winters@uiowa.edu.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winters
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Kristina-thiel@uiowa.edu.
authors.forename: Kristina W
authors.initials: KW
authors.lastname: Thiel
authors.affiliation: 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.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Leslie
authors.affiliation: 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.
authors.forename: Baoli
authors.initials: B
authors.lastname: Yang
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018269:Carcinoma, Endometrioid / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D056827:Endosomal Sorting Complexes Required for Transport / Q000096:biosynthesis / Q000235:genetics*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000075702:Nedd4 Ubiquitin Protein Ligases; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000378:metabolism*; D046888:Tissue Array Analysis; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt
keywords: Endometrial cancer; IGF-1R; Nedd4; PI3K