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Angiogenesis, Metastasis, and the Cellular Microenvironment

Effects of Raf Kinase Inhibitor Protein Expression on Metastasis and Progression of Human Epithelial Ovarian Cancer

¹ Department of Immunology, ² Tianjin Key Laboratory of Cellular and Molecular Immunology, and ³ Department of Pathology, Tianjin Medical University; and ⁴ Department of Oncology, Tianjin Central Maternity Hospital, Tianjin, People's Republic of China

Requests for reprints: Zhi Yao, Department of Immunology, Tianjin Medical University, Heping District Qixiangtai Road No. 22, Tianjin 300070, People's Republic of China. Phone: 86-22-23542817; Fax: 86-22-23542581. E-mail: yaozhi{at}tmu.cn or Jie Yang, Department of Immunology, Tianjin Medical University, Heping District Qixiangtai Road No. 22, Tianjin 300070, People's Republic of China. Phone: 86-22-23542520; Fax: 86-22-23542581. E-mail: yangj{at}tijmu.edu.cn

Loss of function of metastasis suppressor genes is an important step in the progression to a malignant tumor type. Studies in cell culture and animal models have suggested a role of Raf kinase inhibitor protein (RKIP) in suppressing the metastatic spread of prostate cancer, breast cancer, and melanoma cells. However, the function of RKIP in ovarian cancer (OVCA) has not been reported. To explore the potential role of RKIP in epithelial OVCA metastasis, we detected the expression levels of RKIP protein in tissue samples from patients with epithelial OVCA. Consequently, the expression of RKIP is reduced in the poorly differentiated OVCA than in the well-differentiated and moderately differentiated OVCA. In addition, in vitro cell invasion assay indicated that the RKIP expression was inversely associated with the invasiveness of five OVCA cell lines. Consistent with this result, the cell proliferation, anchorage-independent growth, cell adhesion, and invasion were decreased in RKIP overexpressed cells but increased in RKIP down-regulated cells. Further investigation indicated that RKIP inhibited OVCA cell proliferation by altering cell cycle progression rather than promoting apoptosis. Furthermore, the overexpression of RKIP suppressed the ability of human OVCA cells to metastasize when the tumor cells were transplanted into nude mice. Our data show the effect of RKIP on the proliferation, migration, or adhesion of OVCA cells. These results indicate that RKIP is also a metastasis suppressor gene of human epithelial OVCA. (Mol Cancer Res 2008;6(6):917–28)