Reduced Raf-1 kinase inhibitor protein expression predicts less favorable outcomes in patients with hepatic colorectal metastasis

Reduced expression of Raf-1 kinase inhibitor protein (RKIP) has been documented in a number of human malignancies, including colorectal carcinoma (CRC). However, despite the importance of hepatic colorectal metastasis (HCM) for the prognosis of CRC patients, no studies have been conducted regarding RKIP expression in HCM tissues or its prognostic significance. The aim of this study was to clarify the relationship between reduced RKIP expression and HCM and to identify independent predictors for recurrent HCM, which will ultimately help identify patients at high risk of developing metastatic recurrence. An immunohistochemical study of RKIP expression was performed using primary CRC and/or corresponding HCM tissue samples obtained from 117 patients. Forty-nine of these patients did not harbor HCM and 68 harbored HCM. RKIP expression was reduced in 24.5% (12/49) of CRCs without HCM, 47.1% (32/68) of CRCs with HCM and 67.6% (46/68) of HCM. This distribution of RKIP downregulation was statistically significant. RKIP expression was found to independently predict recurrent HCM, with a higher relative risk (6.661) compared to that of nodal metastasis (4.690). A reduction of RKIP expression in HCM was a significant predictor of poor prognosis. The median survival of patients with reduced RKIP expression was 35 months, compared with more than 10 years in patients with positive RKIP expression. Multivariate survival analysis demonstrated that RKIP expression in HCM was an independent predictor of overall survival, with a hazard ratio of 5.161, a value comparable to the risk associated with advanced TNM stage (5.247). We demonstrated that a reduction of RKIP expression in HCM had an independent predictive value for metastatic recurrence and less favorable clinical outcomes in patients with HCM. Our results strongly suggest that patients harboring HCM with reduced RKIP expression require careful monitoring after hepatic resection to detect potentially resectable metastatic recurrences.