E/N-cadherin switch mediates cancer progression via TGF-β-induced epithelial-to-mesenchymal transition in extrahepatic cholangiocarcinoma

Abstract

Background:Epithelial-to-mesenchymal transition (EMT) is a fundamental process governing not only morphogenesis in multicellular organisms, but also cancer progression. During EMT, epithelial cadherin (E-cadherin) is downregulated while neural cadherin (N-cadherin) is upregulated, referred to as ‘cadherin switch'. This study aimed to investigate whether cadherin switch promotes cancer progression in cholangiocarcinoma (CC).Methods:CC cell lines were examined for migration, invasion, and morphological changes with typical EMT-induced model using recombinant TGF-β1. The changes in E-cadherin and N-cadherin expression were investigated during EMT. We also examined E-cadherin and N-cadherin expression in resected specimens from extrahepatic CC patients (n=38), and the associations with clinicopathological factors and survival rates.Results:TGF-β1 treatment activated cell migration, invasion, and fibroblastic morphological changes, especially in extrahepatic CC HuCCT-1 cells. These changes occurred with E-cadherin downregulation and N-cadherin upregulation, that is, cadherin switch. Patients with low E-cadherin expression had a significantly lower survival rate than patients with high E-cadherin expression (P=0.0059). Patients with decreasing E-cadherin and increasing N-cadherin expression had a significantly lower survival rate than patients with increasing E-cadherin and decreasing N-cadherin expression (P=0.017).Conclusion:Cadherin switch promotes cancer progression via TGF-β-induced EMT in extrahepatic CC, suggesting a target for elucidating the mechanisms of invasion and metastasis in extrahepatic CC.

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

“…Ryu et al, did not find any impact of E-cadherin expression on overall survival (OS) or disease free survival (DFS) [24] whereas other groups demonstrated that E-cadherin loss was significantly associated with these parameters and was an independent prognostic factor [25,32,36]. In eCCA, patients with weak E-cadherin expression displayed lower survival rate than patients with high E-cadherin expression [18] and was also an independent prognostic factor [40].…”

“…This switch operates in both types of CCA in which an up-regulation of N-cadherin expression has been observed [18,25,34,40,41]. Increasing N-cadherin expression has been associated with lower OS in both CCA subclasses [25,40] and is an independent unfavorable prognostic factor in eCCA [40].…”

“…A reduction of E-cadherin immunostaining was observed in 16.5-82.1% of iCCA [21, 24-26, 29, 31, 32, 34-36] and eCCA [18,37,39,40]. Although, down-regulation of E-cadherin in iCCA has been correlated with poor tumor differentiation, tumor size, advanced pTNM stage, intrahepatic metastasis and lymph node metastasis [25,26,29,31,32,36], its prognostic value is still controversial.…”

“…While E-cadherin is localized at the plasma membrane in healthy biliary epithelium, its down-regulation and/or ectopic localization, i.e. cytoplasmic internalization, have been reported in malignant cholangiocytes [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Genetic mutations and epigenetic silencing through promoter hypermethylation of the E-cadherin gene (CDH1) are among the mechanisms that account for the down-regulation of E-cadherin [30,33,38].…”

Shikonin as an inhibitor of the LPS-induced epithelial-to-mesenchymal transition in human breast cancer cells

“…N-cadherin is typically expressed by mesenchymal cells, is overexpressed in some cancer cells, and correlates with cell invasiveness (28). Therefore, the loss of E-cadherin expression and the gain of N-cadherin expression in cancer cells have functional significance in cancer progression and metastasis (29).…”