Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer

BACKGROUND. DiminishedexpressionofRafkinaseinhibitorprotein(RKIP),aninhibitorof the Raf signaling cascade, promotes prostate cancer (PCa) metastasis in a murine model, suggestingthatitisametastasissuppressorgene.However,theprognosticsignificanceofRKIP expression and its association with metastasis in PCa patients is unknown. METHODS. To investigate RKIP protein expression is a prognostic marker in PCa we performedimmunohistochemicalstainingforRKIPexpressionintissuemicroarraysconsisting of 758 non-neoplastic prostate tissues, primary tumors and metastases from 134 PCa patients. TheCoxproportional-hazardsmodelwasusedtoadjustforcovariatesincludingGleasonscore, tumor volume, tumor weight, clinical stage, digital rectal exam findings, serum PSA level and surgical margins. RESULTS. RKIP expression was low in approximately 5%, 48%, and 89%of non-neoplastic prostate,primarytumorsandmetastases,respectively.LowRKIPexpressioninprimarytumors was a strong positive predictive factor for PCa recurrence based on PSA levels. In patients whose primary tumors expressed high RKIP levels, the 7-year PSA recurrence rate was <10%; whereas in patients with tumors with low RKIP expression the recurrence rate was 50% (P <0.001). Multivariate analysis revealed RKIP was an independent prognostic factor (P <0.001). CONCLUSION. In contrast to increased expression of pro-tumorigenic genes, these results demonstrate decreased protein expression of a gene, for example, RKIP, can serve as a prognostic marker in PCa patients. Prostate 66: 248–256, 2006. # 2005 Wiley-Liss, Inc.