RAF-kinase inhibitor protein (RKIP) downregulation in esophageal cancer and its metastases

Abstract

Raf kinase inhibitor protein (RKIP) is an inhibitor of Raf-mediated activation of mitogen-activated protein (MAP) kinase (MEK)-MAP kinase and is considered as an important tumor suppressor. RKIP-expression was investigated retrospectively in 321 esophageal cancers [179 adenocarcinomas (ACs), 142 squamous cell carcinomas (SCCs)]. RKIP-expression was further investigated in 41 precursor lesions consisting of 14 cases of non-dysplastic Barrett's mucosa, 5 low grade dysplasias (LGD), and 12 high grade dysplasias (HGD) as well as, 4 cases with low grade and 6 cases with high-grade squamous cell dysplasia. Corresponding lymph node metastases were investigated in 140 patients, distant metastases in 29, and local recurrences in 12. High RKIP-expression was significantly more common in Barrett's mucosa without dysplasia and in LGD compared to HGD (p = 0.047, χ(2) test) and invasive AC (p < 0.001, χ(2) test). In 187 primary esophageal cancers (58.3 %) RKIP was downregulated (AC: 51.4 %; SCC: 66.9 %). RKIP status of primary tumors influenced RKIP expression in corresponding lymph node and distant metastases (p < 0.05, linear regression). Downregulation of RKIP was associated with shorter overall survival (OS) and disease free survival (DFS) in all tumors (p ≤ 0.05, Cox regression). In AC, downregulation of RKIP was an independent prognostic factor for OS and DFS (p ≤ 0.05, Cox regression), while in SCC it reached significance only in univariate analysis (p ≤ 0.05, log-rank test). In conclusion, downregulation of RKIP is associated with shorter survival in esophageal cancers, and RKIP status of tumor cells seems to be preserved at the formation of metastases. Inhibition of RKIP-downregulation might reduce the ability of esophageal cancers to establish disseminated disease.