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KAI1 Metastasis Suppressor Protein Is Down-Regulated during the Progression of Human Endometrial Cancer¹

Division of Gynecologic Oncology, Departments of Obstetrics and Gynecology [F-S. L., Y-T. H., E. S-C. H., M-J. H., C-H. L., L-C. C.] and Pathology [J-T. C.], Taichung Veterans General Hospital, Taichung, Taiwan 40705, Republic of China; Departments of Obstetrics and Gynecology [F-S. L., E. S-C. H.] and Pathology [J-T. C.], Chung Shan Medical University, Taichung, Taiwan 40201, Republic of China; and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322 [J-T. D.]

Purpose: KAI1 is a metastasis suppressor gene located on human chromosome 11p11.2. It is a member of the structurally distinct family of cell surface glycoprotein, transmembrane 4 protein superfamily. KAI1 was initially isolated as a gene that suppressed metastasis of rat prostate tumor cells. Decreased KAI1 expression has been observed recently in various human cancers, including pancreatic, lung, hepatic, colorectal, breast, ovarian, esophageal, and cervical cancers. Frequent down-regulation of the KAI1 protein was also observed in endometrial cancer cell lines. The aim of this study was to determine whether this gene is altered in human endometrial carcinoma. In addition, its prognostic significance in this tumor was also evaluated.

Experimental Design: Tumor specimens from 18 cases with various degrees of endometrial hyperplasia, 97 primary endometrial carcinomas with various stages, and 28 metastatic lesions of this cancer were examined in this study. Using the method of immunohistochemistry, we characterized the KAI1 protein expression in the 143 endometrial tumors. Expression of KAI1 at RNA level was also examined in 35 of the 143 samples using a real-time quantitative PCR method. The data from immunohistochemical analysis were correlated with various clinicopathological factors.

Results: High levels of KAI1 protein expression were detected in almost all of the specimens with endometrial hyperplasia (17 of 18). In contrast, loss of KAI1 expression occurred in an increasing frequency (27.8–71.4%) from early stages of primary endometrial carcinomas to metastatic tumors (P < 0.001). In addition, more poorly differentiated tumors demonstrated significantly lower KAI1 expression as compared with the well-differentiated tumors (P < 0.001). It was also found that patients with KAI1-negative tumors had a lower survival rate than those with KAI1-decreased or positive tumors (P = 0.0042 and 0.0286, respectively). However, in multivariate analysis, the prognostic significance of KAI1 expression was inferior to tumor stage.

Conclusion: These data suggest that KAI1 expression is down-regulated in advanced endometrial cancer. Clinically it may be a useful indicator of the tumor progression and may provide prognostic information on the outcome of this disease.