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Comprehensive multiple molecular profile of epithelial mesenchymal transition in intrahepatic cholangiocarcinoma patients.

Huang XY, Zhang C, Cai JB, Shi GM, Ke AW, Dong ZR, Zhang PF, Fan J, Peng BG, Zhou J - PLoS ONE (2014)

Bottom Line: Cytoplasmic/nuclear β-catenin did not significantly predict worse DFS and was not related with E-cadherin loss.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.These 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.

View Article: PubMed Central - PubMed

Affiliation: The Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, PR China.

ABSTRACT

Background: 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.

Methods: Immunohistochemistry 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.

Results: Reduced 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.

Conclusions: These 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.

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Related in: MedlinePlus

Immunohistochemical analysis of β-catenin in ICC and adjacent nontumorous livers.(A) Representative stainings of negative β-catenin (Case 26, a1, b1), membranous β-catenin (Case 78, a2, b2), cytoplasmic β-catenin (Case 11, a3, b3) and nuclear β-catenin (Case 104, a4, b4) in adjacent nontumorous liver tissues (a1, a2, a3, a4) and ICC tissues (b1, b2, b3, b4) were illustrated. Magnification ×200. (B, C) Kaplan-Meier survival analysis of OS and DFS in ICCs with negative/membranous expression of β-catenin versus cytoplasmic/nuclear expression of β-catenin expression.
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pone-0096860-g002: Immunohistochemical analysis of β-catenin in ICC and adjacent nontumorous livers.(A) Representative stainings of negative β-catenin (Case 26, a1, b1), membranous β-catenin (Case 78, a2, b2), cytoplasmic β-catenin (Case 11, a3, b3) and nuclear β-catenin (Case 104, a4, b4) in adjacent nontumorous liver tissues (a1, a2, a3, a4) and ICC tissues (b1, b2, b3, b4) were illustrated. Magnification ×200. (B, C) Kaplan-Meier survival analysis of OS and DFS in ICCs with negative/membranous expression of β-catenin versus cytoplasmic/nuclear expression of β-catenin expression.

Mentions: Our observation that enhanced E-cadherin and Vimentin expression were significantly correlated with ICC prognosis raised the question whether the EMT regulators β-catenin, snail and slug might play a similar role in the progression of ICC in humans. The EMT of tumor cells is associated with a nuclear accumulation of the transcriptional activator β-catenin. β-catenin is a major E-cadherin-binding protein at cellular junctions and acts as a key mediator of the Wnt signaling pathway. In the present study, we compared β-catenin immunostaining in 140 ICC patients. Intense staining for β-catenin in nontumorous hepatocytes was mainly located at the membrane (Figure 2A). β-catenin expression patterns in tumors were highly variable (Figure 2A). Of 140 ICC patients, 76 (54.3%) showed negative or membranous expression of β-catenin, and 64 (45.7%) showed cytoplasmic or nuclear expression of β-catenin. β-catenin expression was not correlated with clinicopathological features (Table S2). OS and DFS were estimated by Kaplan-Meier curves. Regarding OS, β-catenin expression was significantly associated with the prognosis of patients with ICC (P = 0.046, Figure 2B). In particular, 43.4% of patients in the group with negative or membranous expression of β-catenin died within 12 months after curative resection compared with 50.0% of patients in the group with cytoplasmic or nuclear expression of β-catenin. However, the expression patterns of β-catenin were not related to the DFS of ICC patients (Figure 2C, P = 0.198).


Comprehensive multiple molecular profile of epithelial mesenchymal transition in intrahepatic cholangiocarcinoma patients.

Huang XY, Zhang C, Cai JB, Shi GM, Ke AW, Dong ZR, Zhang PF, Fan J, Peng BG, Zhou J - PLoS ONE (2014)

Immunohistochemical analysis of β-catenin in ICC and adjacent nontumorous livers.(A) Representative stainings of negative β-catenin (Case 26, a1, b1), membranous β-catenin (Case 78, a2, b2), cytoplasmic β-catenin (Case 11, a3, b3) and nuclear β-catenin (Case 104, a4, b4) in adjacent nontumorous liver tissues (a1, a2, a3, a4) and ICC tissues (b1, b2, b3, b4) were illustrated. Magnification ×200. (B, C) Kaplan-Meier survival analysis of OS and DFS in ICCs with negative/membranous expression of β-catenin versus cytoplasmic/nuclear expression of β-catenin expression.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016113&req=5

pone-0096860-g002: Immunohistochemical analysis of β-catenin in ICC and adjacent nontumorous livers.(A) Representative stainings of negative β-catenin (Case 26, a1, b1), membranous β-catenin (Case 78, a2, b2), cytoplasmic β-catenin (Case 11, a3, b3) and nuclear β-catenin (Case 104, a4, b4) in adjacent nontumorous liver tissues (a1, a2, a3, a4) and ICC tissues (b1, b2, b3, b4) were illustrated. Magnification ×200. (B, C) Kaplan-Meier survival analysis of OS and DFS in ICCs with negative/membranous expression of β-catenin versus cytoplasmic/nuclear expression of β-catenin expression.
Mentions: Our observation that enhanced E-cadherin and Vimentin expression were significantly correlated with ICC prognosis raised the question whether the EMT regulators β-catenin, snail and slug might play a similar role in the progression of ICC in humans. The EMT of tumor cells is associated with a nuclear accumulation of the transcriptional activator β-catenin. β-catenin is a major E-cadherin-binding protein at cellular junctions and acts as a key mediator of the Wnt signaling pathway. In the present study, we compared β-catenin immunostaining in 140 ICC patients. Intense staining for β-catenin in nontumorous hepatocytes was mainly located at the membrane (Figure 2A). β-catenin expression patterns in tumors were highly variable (Figure 2A). Of 140 ICC patients, 76 (54.3%) showed negative or membranous expression of β-catenin, and 64 (45.7%) showed cytoplasmic or nuclear expression of β-catenin. β-catenin expression was not correlated with clinicopathological features (Table S2). OS and DFS were estimated by Kaplan-Meier curves. Regarding OS, β-catenin expression was significantly associated with the prognosis of patients with ICC (P = 0.046, Figure 2B). In particular, 43.4% of patients in the group with negative or membranous expression of β-catenin died within 12 months after curative resection compared with 50.0% of patients in the group with cytoplasmic or nuclear expression of β-catenin. However, the expression patterns of β-catenin were not related to the DFS of ICC patients (Figure 2C, P = 0.198).

Bottom Line: Cytoplasmic/nuclear β-catenin did not significantly predict worse DFS and was not related with E-cadherin loss.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.These 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.

View Article: PubMed Central - PubMed

Affiliation: The Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, PR China.

ABSTRACT

Background: 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.

Methods: Immunohistochemistry 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.

Results: Reduced 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.

Conclusions: These 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.

Show MeSH
Related in: MedlinePlus