title: Rap1GAP inhibits tumor progression in endometrial cancer.
abstract: Endometrioid adenocarcinoma (EAC) is a common endometrial cancer with recent dramatic increases in incidence. Previous findings indicate that Rap1GAP acts as a tumor suppressor inhibiting Ras superfamily protein Rap1 in multiple aggressive carcinomas; however, Rap1GAP expression in EAC has not been investigated. In this study, the tumor suppressing activity of Rap1GAP in EAC was explored.
  
  
  
  EAC cell lines were used to examine Rap1GAP levels by real-time RT-PCR and western blotting and the effects of Rap1GAP on cancer cell invasion and migration. Rap1GAP expression was analyzed by immunohistochemical staining for Rap1GAP, E-cadherin in surgically resected tumors of 114 EAC patients scored according to EAC differentiation grade. Prognostic variables such as age, stage, grade, tumor size, and immunostaining for Rap1GAP, E-cadherin were evaluated using Cox regression multivariate analysis.
  
  
  
  Low Rap1GAP expression was detected in poorly differentiated EAC cells. Rap1GAP deficiency significantly accelerated while Rap1 deficiency decreased cancer cell migration and invasion. Patients with higher Rap1GAP, E-cadherin, and especially combined Rap1GAP/E-cadherin levels had better overall survival than EAC patients with no or weak expression. In addition, Rap1GAP expression was an independent prognostic factor in EAC.
  
  
  
  Inhibition of Rap1GAP expression increases EAC cell migration and invasion through upregulation of Rap1. Low expression of Rap1GAP correlates with poor EAC differentiation. Our findings suggest that Rap1GAP is an important tumor suppressor with high prognostic value in EAC.
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South1 West16, Chuo-ku, Sapporo, Hokkaido, Japan. Electronic address: mtamate@sapmed.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Tamate
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South1 West16, Chuo-ku, Sapporo, Hokkaido, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South1 West16, Chuo-ku, Sapporo, Hokkaido, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osogami
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South1 West16, Chuo-ku, Sapporo, Hokkaido, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Matsuura
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South1 West16, Chuo-ku, Sapporo, Hokkaido, Japan.
authors.forename: Seiro
authors.initials: S
authors.lastname: Satohisa
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South1 West16, Chuo-ku, Sapporo, Hokkaido, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwasaki
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South1 West16, Chuo-ku, Sapporo, Hokkaido, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015820:Cadherins; D020690:GTPase-Activating Proteins; C484658:RAP1GAP protein, human
keywords: E-cadherin; Endometrial carcinoma; Endometrioid adenocarcinoma; Rap1GAP; Tumor suppressor