Epithelial-mesenchymal transition-related protein expression in biliary epithelial cells associated with hepatolithiasis.
OBJECTIVE
Epithelial-mesenchymal transition (EMT) of biliary epithelial cells (BECs) plays major roles in many cholangiopathies. This study evaluated whether EMT of BECs has a role in hepatolithiasis-induced biliary fibrosis and types of BECs that are involved.


METHODS
The expression of EMT-related proteins and epidermal growth factor receptor was evaluated by immunohistochemistry of liver tissues from 102 patients with hepatolithiasis, 32 patients with post-hepatitis cirrhosis, and 48 normal livers. Antibodies against E-cadherin, β-catenin, and cytokeratin were used to identify epithelial cells and antibodies against vimentin, S100A4, podoplanin, and α-smooth muscle actin (α-SMA) were used to identify mesenchymal cells. The relationship between clinical and histological parameters and immunohistochemistry findings in BECs, and the surrounding stroma were evaluated.


RESULTS
Loss of E-cadherin and acquisition of S100A4 and vimentin were observed in BECs. In all BECs, cytokeratin and β-catenin expression were unchanged, while podoplanin and α-SMA were not expressed. Although hepatic fibrosis was more severe in post-hepatitis cirrhosis, EMT of BECs was more widespread in hepatolithiasis. In hepatolithiasis, EMT-related proteins were more highly expressed in small bile ducts than in medium or large bile ducts. Their expression was associated with the severity of biliary fibrosis and the expressions of epidermal growth factor receptor. Expression of α-SMA in fibroblasts from the portal space was closely linked to pathological changes in small bile ducts and EMT-related protein expressions in BECs.


CONCLUSIONS
Proliferating cholangiocytes that form small bile ducts may contribute to cholangiopathies in hepatolithiasis through an EMT-like phenomenon or through interactions with stromal myofibroblasts.
Department of Pathology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Korea.
Rohyun
R
Sung
Sang Hwa
SH
Lee
Meiying
M
Ji
Joung-Ho
JH
Han
Min Ho
MH
Kang
Ji Hoon
JH
Kim
Jae-Woon
JW
Choi
Young Chul
YC
Kim
Seon Mee
SM
Park
D000199:Actins / Q000235:genetics* / Q000378:metabolism*; D000368:Aged; D001652:Bile Ducts / Q000166:cytology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D020347:Lithiasis / Q000235:genetics* / Q000473:pathology*; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
C541116:ACTA2 protein, human; D000199:Actins; D015820:Cadherins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D014746:Vimentin; C077591:S100A4 protein, human
EGFR; biliary epithelial cell; epithelial-mesenchymal transition; hepatolithiasis