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

Abstract

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)

RKIP inhibits the malignant phenotypes of gastric cancer cells

“…MAPK signaling is well known to be negatively regulated by several regulators such as protein tyrosine phosphatase. RKIP is a newly identified negative regulator of MAPK signaling and it is not surprising that RKIP is downregulated in different types of cancer [11][12][13][14]. Especially, recent studies reported that RKIP expression was lower in gastric carcinoma than in normal gastric tissue and loss of RKIP expression was associated with tumour progression and poor survival of gastric cancer [15,16].…”

Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients

“…Subsequent studies showed that overexpression of RKIP in prostate and melanoma cell lines suppresses metastasis by decreasing vascular invasion (18,20). Previous studies have described low levels of RKIP in other metastatic tumors, such as breast and colorectal carcinoma (23,45), as well as in many other primary tumors, including GISTs (27), insulinoma (22), hepatocarcinoma (24), ovarian carcinoma (26), merckel cell carcinoma (16) and thyroid carcinoma (15), cutaneous squamous cell carcinoma (46) and nasopharyngeal carcinoma (17). Furthermore, loss of cytoplasmic RKIP has also been associated with poor prognosis in prostate, colorectal, GISTs and glial tumors (25,(27)(28)(29)(30).…”

“…In cancer, RKIP is considered to be a signal transduction modulator and a metastasis suppressor (14), and down regulated in several human tumors, mainly in highly metastatic carcinomas (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Noteworthy, RKIP has been shown to be a prognostic marker in prostate cancer, colorectal carcinomas, gliomas and GISTs (25,(27)(28)(29)(30).…”

Loss of RAF kinase inhibitor protein is a somatic event in the pathogenesis of therapy-related acute myeloid leukemias with C-RAF germline mutations

“…Although we were unable to measure RKIP mRNA expression levels owing to the shortage of leukemic samples, a concomitant decrease in both RKIP protein and mRNA expression has been shown in various solid tumors. 11,12 We then searched for mechanisms underlying decreased RKIP expression in t-AML. The coding region of RKIP was sequenced for inactivating mutations and the DNA copy number assessed to screen for gene deletions.…”