Abstract

Epithelial-mesenchymal transition (EMT) plays a pivotal role in cancer invasion and metastasis, and transforming growth factor (TGF)-β signaling is a potent inducer of EMT. However, the clinical significance of the correlation between EMT marker expression and TGF-β signaling in hepatocellular carcinoma (HCC) patients remains unknown. In this study, immunohistochemistry was used to analyze the expression of EMT markers and phospho-Smad2 nuclear positivity, and their association with clinicopathological features in 150 HCC patients. E-cadherin(high)/vimentin(low) and E-cadherin(low)/vimentin(high) expression profiles were determined in 55 (36.7%) and 21 (14.0%) patients, respectively. The E-cadherin(low)/vimentin(high) expression profile was significantly correlated with poor tumor differentiation (P<0.001), vascular invasion (P=0.007) and extrahepatic recurrence following curative surgery (P=0.026). Furthermore, the E-cadherin(low)/vimentin(high) expression profile was significantly correlated with shorter disease-free survival compared to E-cadherin(high)/vimentin(low) (P=0.002). Forty-one patients (27.3%) were demonstrated to have high phospho-Smad2 nuclear positivity, which was significantly correlated with the E-cadherin(low)/vimentin(high) expression profile (P<0.001). In conclusion, this study suggests that EMT expression profiles are useful prognostic markers for disease-free survival in HCC patients, and that the E-cadherin(low)/vimentin(high) expression profile is closely associated with high-grade malignant behavior such as tumoral vascular invasion and metastasis in HCC. Additionally, TGF-β-mediated EMT may play an important role in the aggressiveness of HCC.

Highlights

  • Hepatocellular carcinoma (HCC) is the fifth most prevalent and third most fatal type of cancer worldwide, and is currently diagnosed in over half a million people each year globally [1]

  • We assessed the clinical relevance of transforming growth factor (TGF)‐β signaling in patients with HCC by IHC analysis of phospho‐Smad2; 41 (27.3%) of 150 patients showed high phospho‐Smad2 nuclear positivity

  • To investigate the clinical association between the Epithelial-mesenchymal transition (EMT) marker profiles and TGF‐β signaling, phospho‐Smad2 nuclear positivity was compared between the subgroups with an E‐cadherinhigh/vimentinlow or E‐cadherinlow/vimentinhigh expression profile

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Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most prevalent and third most fatal type of cancer worldwide, and is currently diagnosed in over half a million people each year globally [1]. A correlation between the expression profiles of EMT and EMT inducers, and tumor recurrence and distant metastasis, has been demonstrated in certain types of cancer, including breast and colon cancer [3,4]. Transforming growth factor (TGF)‐β signaling plays a central role in tumorigenesis and tumor progression by regulating many critical cellular processes, including cell proliferation, apoptosis and EMT. MIMA et al: TGF-β-MEDIATED EMT IN HCC between the expression profiles of EMT markers and TGF‐β signaling, and its significance in HCC patients remains to be elucidated. We investigated the expression of the EMT markers E‐cadherin and vimentin (epithelial and mesenchymal markers, respectively) and phospho‐Smad by immunohistochemical (IHC) analyses. The clinical significance of the expression profiles and TGF‐β signaling in HCC patients were further assessed

Materials and methods
Results
Discussion
El‐Serag HB
Siegel PM and Massagué J
Liver Cancer Study Group of Japan

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