Abstract
BackgroundThe aim of this study is to investigate the expression profile of multiple epithelial mesenchymal transition (EMT)-related molecules in intrahepatic cholangiocarcinoma (ICC) and the related prognostic significance.MethodsImmunohistochemistry was performed to determine the expression of E-cadherin, Vimentin, Snail, slug and β-catenin in a tissue microarray consisting of tumor tissues of 140 ICC patients undergoing curative resection. The correlation between the expression of these molecules and the clinicopathological characteristics of ICC patients was analyzed, and their prognostic implication was evaluated.ResultsReduced E-cadherin and increased Vimentin expression, the characteristic changes of EMT, identified in 55.0% and 55.7% of primary ICCs, respectively, were correlated with lymphatic metastasis and poorer overall survival (OS) and disease-free survival (DFS) of ICCs. The overexpression of snail and nonmembranous β-catenin, which are the major regulators of the EMT, were identified in 49.2% and 45.7% of primary ICCs, while little slug expression was detected in ICCs. Cytoplasmic/nuclear β-catenin did not significantly predict worse DFS and was not related with E-cadherin loss. The overexpression of snail predicted worse OS and DFS. Snail overexpression correlated with the down-regulation of E-cadherin and the up-regulation of Vimentin. Inhibition of snail in an ICC cell line decreased the expression of E-cadherin, enhanced the expression of Vimentin and impaired the invasion and migration ability of ICC cells.ConclusionsThese data support the hypothesis that EMT plays vital roles in ICC progression and suggest that snail but not slug and β-catenin plays a crucial role in the EMT induction of ICC.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is a form of aggressive malignancies that arise in the biliary tract and are challenging to diagnose, prevent or treat [1]
For the diseasefree survival (DFS) analyses, negative E-cadherin expression was significantly associated with higher recurrence (Figure 1B)
Lymphatic metastasis was found to associate with high levels of Vimentin expression (Table S1)
Summary
Intrahepatic cholangiocarcinoma (ICC) is a form of aggressive malignancies that arise in the biliary tract and are challenging to diagnose, prevent or treat [1]. Characteristic alterations that occur during EMT include down-regulation of epithelial markers (e.g., E-cadherin and plakoglobin) and upregulation of mesenchymal markers (e.g., Vimentin and Ncadherin) [3]. The suppression of E-cadherin expression by the major EMT regulators initiates the EMT process [3]. Zinc-finger transcriptional repressors, are two strong repressors of E-cadherin gene transcription, and the accumulation of Snail and slug in nuclei strongly represses the expression of Ecadherin, which triggers the EMT of the cancer cells [3,4]. The aim of this study is to investigate the expression profile of multiple epithelial mesenchymal transition (EMT)-related molecules in intrahepatic cholangiocarcinoma (ICC) and the related prognostic significance
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