Prognostic value of multiple epithelial mesenchymal transition‑associated proteins in intrahepatic cholangiocarcinoma

Abstract

The aim of the present study was to investigate the expression of epithelial mesenchymal transition (EMT)-associated proteins and their prognostic value in intrahepatic cholangiocarcinoma (ICC). The expression of six EMT-associated proteins, including E-cadherin, N-cadherin, Vimentin, Snail family transcriptional repressor 1 (Snail), Snail family transcriptional repressor 2 (Slug) and S100 calcium binding protein A4 (S100A4) was determined by immunohistochemistry in 109 patients with ICC who had received surgery. Survival analysis showed that patients with low E-cadherin expression (P<0.001) or high S100A4 (P<0.001) or Snail (P<0.001) expression had a reduced survival time. Based on the numbers of alterations in the expression of EMT-associated proteins as determined by immunohistochemical analysis, the patients were categorized as low (score, 0-3; n=75) or high (score, ≥4; n=34) EMT expression groups. The high EMT expression group was significantly associated with positive lymph node metastasis (P=0.023) and late Tumor-Node-Metastasis (TNM) stage (P<0.001). Furthermore, patients in the high EMT expression group had a significantly poorer overall survival time than those in the low EMT expression group (P<0.001). Multivariate analysis indicated that EMT status was a significant independent predictor for overall survival time (P=0.004), and was linked to surgical margin (P=0.013) and TNM stage (P<0.001). In conclusion, the reduced expression of E-cadherin and high expression of Snail and S100A4 were significantly associated with the poor survival of patients with ICC after surgery. The EMT protein expression status was associated with ICC progression, and may be considered as an independent prognostic indicator for patients with ICC.

N-Cadherin Distinguishes Intrahepatic Cholangiocarcinoma from Liver Metastases of Ductal Adenocarcinoma of the Pancreas

“…In another study, immunohistochemical examination of iCCA showed a significantly lower expression of E-cadherin than in adjacent tissue and normal bile duct tissue, confirming our results [57]. Reduction of immunohistochemical E-cadherin expression in iCCA compared to normal tissue has been reported in many studies, often correlating with a higher tumor grade [58][59][60][61][62]. We, therefore, suggest that the downregulation of E-and N-cadherins in BTC is a general phenomenon of dedifferentiation, as it is also commonly observed for various other immunohistochemical marker proteins.…”

S100A8 and S100A9, both transcriptionally regulated by PU.1, promote epithelial-mesenchymal transformation (EMT) and invasive growth of dermal keratinocytes during scar formation post burn

“…Snail (encoded by SNAI1 gene) is a family of Zinc finger proteins and transcription factors that promote the repression of the adhesion molecule E-cadherin to regulate EMT during embryonic development and many pathological processes [20]. Many members of S100 family, including S100A8 and S100A9, have been involved in EMT in multiple types of cells [21][22][23][24]: S100A4 was associated with expression of Snail in human cancers and atrial fibrillation. In this study, we identified S100A8 and S100A9 as positive regulators of Snail, enhancing its phosphorylation and nuclear translocation to promote EMT of epidermal keratinocytes and scar development in vivo.…”

Peptidylarginine Deiminase Type 2 Predicts Tumor Progression and Poor Prognosis in Patients with Curatively Resected Biliary Tract Cancer

“…PADI2 has been shown to promote EMT during ovarian cancer progression [ 14 ] and skin neoplasms [ 35 ]. The involvement of EMT processes in cholangiocarcinoma has been proposed previously [ 36 , 37 ]. Moreover, consistent over-expression of EMT-related features has been shown to correlate with poor prognosis in advanced BTC [ 38 ].…”