Rap1GAP inhibits tumor progression in endometrial cancer
Masato Tamate1, Ryoichi Tanaka1, Hiroyuki Osogami1
1Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South1 West16, Chuo-ku, Sapporo, Hokkaido, Japan.
Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Rap1GAP acts as a tumor suppressor in endometrioid adenocarcinoma (EAC), inhibiting cancer cell migration and invasion. Low Rap1GAP expression correlates with poor EAC differentiation and predicts worse survival, highlighting its prognostic value.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Endometrioid adenocarcinoma (EAC) incidence is rising.
- Rap1GAP is a known tumor suppressor in other cancers, but its role in EAC is unstudied.
Purpose of the Study:
- To investigate the tumor-suppressing role of Rap1GAP in EAC.
- To determine the prognostic significance of Rap1GAP expression in EAC patients.
Main Methods:
- Real-time RT-PCR and western blotting assessed Rap1GAP levels in EAC cell lines.
- Immunohistochemical staining for Rap1GAP and E-cadherin was performed on 114 EAC patient tumors.
- Cox regression analysis evaluated prognostic variables.
Main Results:
- Low Rap1GAP expression was found in poorly differentiated EAC cells.
- Rap1GAP deficiency enhanced cancer cell migration and invasion.
- Higher Rap1GAP and E-cadherin levels correlated with improved overall survival and were independent prognostic factors.
Conclusions:
- Rap1GAP functions as a tumor suppressor in EAC by inhibiting cell migration and invasion.
- Low Rap1GAP expression is linked to poor differentiation and serves as a significant prognostic marker in EAC.
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