Aberrant expression of trefoil factor family 1 in biliary epithelium in hepatolithiasis and cholangiocarcinoma.
Stepwise progression of intrahepatic cholangiocarcinoma (ICC) has been proposed in hepatolithiasis. We examined the participation of trefoil factor family 1 (TFF1), which is critical for mucosal protection and tumor suppression in the stomach, in the development and progression of ICC. We used 16 livers of ICC with hepatolithiasis, 11 of biliary epithelial dysplasia with hepatolithiasis, 16 of hepatolithiasis without dysplasia or carcinoma, 18 of ICC without hepatolithiasis, and 39 control livers. TFF1 expression in the biliary epithelium was increased in hepatolithiasis compared with control livers (p < 0.01). In biliary epithelial dysplasia and noninvasive ICC with hepatolithiasis, TFF1 was extensively expressed and MUC5AC gastric mucin was usually colocalized with TFF1. However, TFF1 expression was significantly decreased in invasive ICC despite preserved expression of MUC5AC. A total of four missense mutations were detected: three in two noninvasive ICC with hepatolithiasis (28.6%) and one in invasive ICC (11%). Loss of heterozygosity of the TFF1 gene was not detectable. The decreased expression of TFF1 in invasive ICC may be explained by the methylation of the TFF1 promoter region. Up-regulation of TFF1 coupled with MUC5AC in biliary epithelium in hepatolithiasis, biliary epithelial dysplasia, and noninvasive ICC may reflect the gastric metaplasia and early neoplastic lesion. Under such conditions, decreased TFF1 expression may lead to increased cell proliferation and then to the invasive character of ICC.
Sasaki
Motoko
M
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Tsuneyama
Koichi
K
Nakanuma
Yasuni
Y
D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D001659:Biliary Tract / Q000378:metabolism* / Q000473:pathology; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002769:Cholelithiasis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011506:Proteins; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins
D004273:DNA, Neoplasm; D006133:Growth Substances; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D010455:Peptides; D011506:Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins