Expression of apomucins in the intrahepatic biliary tree in hepatolithiasis differs from that in normal liver and extrahepatic biliary obstruction

Abstract

Mucin plays an important role in the development of hepatoliths, which are formed within the intrahepatic large bile ducts. To date, eight apomucins, components of mucin, have been identified. The purpose of this study is to characterize the expression of MUC1, MUC2, MUC3, MUC5, and MUC6 apomucins at both the protein and messenger RNA (mRNA) levels in the intrahepatic large bile ducts and peribiliary glands in 36 livers from patients with hepatolithiasis, in 25 livers from the patients with extrahepatic biliary obstruction, and in 23 histologically-normal livers. MUC3 and MUC6 were constantly and focally expressed, respectively, in the biliary epithelial cells in the intrahepatic large bile ducts in normal livers, extrahepatic biliary obstruction, and, also, hepatolithiasis. In hepatolithiasis, MUC1, MUC2, and MUC5 apomucins were also focally expressed in 33%, 64%, and 89%, respectively, of the large intrahepatic bile ducts examined, whereas such expression was infrequent in normal livers and in extrahepatic biliary obstruction. The markedly proliferated intramural and extramural peribiliary glands in hepatolithiasis frequently expressed MUC3 and MUC6 apomucins and focally expressed MUC2 and MUC5 apomucins. All of the apomucins mRNA expression, except that of MUC1, resembled each protein expression. In conclusion, the characteristics of apomucins in the intrahepatic biliary tree in hepatolithiasis differs from those in normal livers and extrahepatic biliary obstructrion. Increased expression of gel-forming mucins, such as MUC5 and MUC2, could be involved in the formation and development of hepatolithiasis. (HEPATOLOGY 1998;27:46-53.)Epithelial mucins and their alterations are involved in the pathogenesis of neoplastic and non-neoplastic diseases. These mucins have in common a protein backbone which is generally called apomucin or mucin core protein. 1 To date, eight apomucins (MUC 1-7 and MUC5B) have been identified 2-8 and the tissue-and cell-specific expression of these mucin genes is now emerging, suggesting that each has a distinct role. [9][10][11][12][13][14][15][16][17][18][19]

Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasis

“…14,16 In the present study, MUC5AC was expressed widely and MUC2 focally in reference cases of IPNL. Mucinous ICC associated with hepatolithiasis expressed both MUC2 and MUC5AC frequently.…”

“…We have reported that aberrant expression of MUC5AC frequently occurs in the biliary mucosa in hepatolithiasis, and biliary epithelial dysplasia and IPNL. 14,17,37 The aberrant expression of MUC5AC has also reportedly been seen in the early step of pancreatic carcinoma. 38 Therefore, aberrant expression of MUC5AC may be a common feature suggesting the early step of carcinogenesis in epithelial cells of intrahepatic bile ducts and pancreatic ducts.…”

“…We reported previously that IPNL with and without mucinous ICC and chronic proliferative cholangitis associated with hepatolithiasis frequently present a gastric or intestinal differentiation characterized by the aberrant expression of MUC2 and MUC5AC, 13,14 Given that the aberrant expression of CDX2 causes an intestinal differentiation with MUC2 expression in the stomach and esophagus, it is conceivable that CDX2 may be involved in the development of intestinal differentiation in the intrahepatic biliary tree in hepatolithiasis. 13 However, it remains unclear whether or not the transcription of intestinal genes including MUC2 is regulated by CDX2 in IPNL and mucinous ICC.…”

Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture

“…In hepatolithiasis, the intrahepatic bile ducts show chronic cholangitis and intestinal metaplasia with goblet cells and aberrant MUC2 expression, and many kinds of bacteria species, especially Escherichia coli, were detected in bile of the affected ducts. [14][15][16] MUC2 is reportedly overexpressed in response to bacterial components, such as LPS or LTA, in cultured intestinal or airway epithelial cells and also BECs. 21,27,28 Therefore, it is possible that bacterial infection and/or bacterial components are responsible for the intestinal metaplasia and MUC2 expression in the affected ducts in hepatolithiasis.…”

“…For example, in chronic cholangitis such as hepatolithiasis, intestinal metaplasia with goblet cells occurs, and MUC2 is aberrantly expressed in goblet cells colocalized with CDX2. 1,[10][11][12][13][14][15][16][17][18] Bacterial infections are implicated in chronic cholangitis with intestinal metaplasia. 19,20 Lipopolysaccharide (LPS), a bacterial component, is known to cause MUC2 overexpression in cultured biliary epithelial cells (BECs).…”