Inverse correlation between RKIP and STAT3 expression and clinical outcome of gastric adenocarcinoma patients

Abstract

1964

The Raf Kinase Inhibitory Protein (RKIP) is a member of the phosphatidylethanolamine-binding protein family and is a negative regulator of the mitogen-activated protein kinase cascade initiated by Raf-1. RKIP is also considered to play a pivotal role in cancer, regulating apoptosis induced by chemotherapeutic agents, or immune-mediated stimuli. Recent studies have shown that RKIP is a novel and clinically relevant metastasis suppressor gene of prostate, breast, and melanoma human tumor models. As opposed to RKIP, the signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a critical role in cytokine and growth factor signaling and is frequently activated in human tumors, including gastric adenocarcinomas, thus favoring tumor growth. STAT3 protein constitutive activation and nuclear localization have been associated with the induction of cell cycle, anti-apoptotic and metastasis-related genes. Significantly, cytokine-mediated activation of STAT3 in human tumor models results in proteosome-dependent loss of RKIP expression. The purpose of our study was to evaluate the role of RKIP in predicting survival in gastric adenocarcinoma patients. Validation of the results was done by assessing the relationship between RKIP and STAT3 expression and patient survival. Tissue microarrays were created from paraffinized samples from 136 patients with gastric adenocarcinomas, 60 intestinal subtype and 76 diffuse or mixed subtypes. The microarrays were immunohistochemically stained for RKIP and STAT3 and the intensity of staining was semiquantitatively scored. Our results indicate that in the intestinal tumor type, RKIP and STAT3 were inversely associated (p=0.02, OR=0.19). Thus, RKIP positively correlated with patient survival (the survival rates: in RKIP positive (+) cases: 71%. In RKIP negative (-) cases: 35%, p=0.029). STAT3 negatively correlated with survival (STAT3+ cases: 23%, STAT3- cases: 55%, p=0.042). In the diffuse tumor type, no significant correlation was found between RKIP and patient outcome (p=0.23). In the intestinal type of adenocarcinoma, multivariate analysis adjusted for treatment types, revealed RKIP, STAT3 and tumor stage to be significant independent predictors of survival (p=0.031, p=0.037 and p=0.001, respectively). In the diffuse tumor type, stage was the only significant predictor of survival (p=0.004). These results indicate the predictive and protective role of RKIP in gastric adenocarcinoma of the intestinal subtype and are the first to demonstrate the association between RKIP and STAT3 expression. Notably, the data indicate an inverse association between RKIP and STAT3 and a positive correlation between RKIP and patient survival.