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.

Loss of Raf-1 kinase inhibitor protein (RKIP) is strongly associated with high-grade tumor budding and correlates with an aggressive phenotype in pancreatic ductal adenocarcinoma (PDAC)

“…This implies that progressive RKIP loss may play a key role in the pancreatic neoplastic transformation and that it is taking place even before invasion occurs. Similar findings were observed in a previous study concerning esophageal Barrett mucosa, where a down-regulation of RKIP was found in high-grade dysplasia compared with non-dysplastic lesions [32]. Our findings are partially in keeping with previous studies on RKIP expression on pancreatic cancer, which have also demonstrated a significant RKIP loss in cancer tissues compared with normal pancreatic tissue and an association of RKIP loss with presence of nodal and/or distant metastases as well as reduced patient survival [33,34].…”

RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact

“…Several studies have shown that RKIP exhibits low expression levels in various cancers and it is often absent in metastasis [8,9,17,19,43,45,48,49,50,51,52,53,54,55,56,57,58,59,60]. RKIP loss has been suggested to result by hypermethylation of its promoter [41].…”

Promoter methylation and expression of Raf kinase inhibitory protein in esophageal squamous cell carcinoma

“…In addition, Gao et al reported that positive expression of RKIP in ESCC occurred significantly less often than in paratumor normal tissues, and that reduced RKIP expression was significantly correlated with a higher risk of recurrence, implying its importance in prognosis prediction (16). Furthermore, the expression level of RKIP was decreased in the order of dysplastic Barrett's mucosa, low-grade dysplasia, high-grade dysplasia and EAC, suggesting its involvement in esophageal carcinogenesis (17).…”