Expression Profiles of MUC Mucin Core Protein in the Intrahepatic Biliary System: Physiological Distribution and Pathological Significance

Abstract

Mucin secreted by mucosal epithelial cells plays a role in the protection of the mucosal surface and also is involved in pathological processes. So far, MUC1-4, 5AC, 5B, 6-8, 11-13 and 15-17 genes coding the backbone mucin core protein have been identified in humans. Their diverse physiological distribution and pathological alterations have been reported. We have studied the expression profiles of MUC genes in the intrahepatic biliary system in developmental, normal and diseased livers using immunohistochemistry and in situ hybridization. Fetal intrahepatic bile ducts and ductal plates frequently express MUC1, while intrahepatic large bile ducts after birth express mainly MUC3 mucin. In hepatolithiasis, MUC5AC (gastric foveolar epithelial type) and MUC6 (pyloric gland type) mucins are newly expressed in surface epithelial cells and proliferated peribiliary glands, respectively, and the expression of gel-forming mucin may play a role in lithogenesis. Most biliary epithelial dysplasias and cholangiocarcinomas associated with hepatolithiasis expressed MUC5AC, suggesting that intrahepatic bile ducts express the gastric foveolar phenotype during carcinogenesis. In addition, intestinal metaplasia, intraductal papillary tumor and mucinous carcinoma, characterized by MUC2 expression, are occasionally associated with hepatolithiasis in a CDX2 homeobox gene-dependent manner. These findings may suggest the presence of intestinal metaplasia-related carcinogenesis in the intrahepatic biliary system as in the stomach.

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

“…The distribution of MUC2 and CDX2 expression is similar to that in previous reports in that MUC2 expression is restricted to the cytoplasm of goblet type cells and CDX2 is expressed extensively compared with MUC2. 1,8,17 CDX2 expression may be an early event in intestinal metaplasia because the expression of MUC2 is found within BECs that express CDX2. The extensive expression of CDX2 might suggest that CDX2 exists upstream in the pathogenesis of intestinal metaplasia.…”

“…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).…”

Mucin expression profile in pancreatic cancer and the precursor lesions

“…Mucins are high molecular weight glycoproteins with oligosaccharides attached to serine or threonine residues of the mucin core protein backbone by O ‐glycosidic linkages, which are produced by various epithelial cells. Core proteins for human mucins (MUC1‐MUC9, MUC11–13, MUC15–20) have been identified recently . Mucins are categorized into membrane‐associated mucins (MUC1, MUC3 MUC4, MUC12, MUC16, and MUC17), gel‐forming mucins (MUC2, MUC5AC, MUC5B, and MUC6), and soluble mucin (MUC7) …”

“…Core proteins for human mucins (MUC1-MUC9, MUC11-13, MUC15-20) have been identifi ed recently. [2][3][4][5][6][7][8][9][10][11][12][13] Mucins are categorized into membraneassociated mucins (MUC1, MUC3 MUC4, MUC12, MUC16, and MUC17), gel-forming mucins (MUC2, MUC5AC, MUC5B, and MUC6), and soluble mucin (MUC7). 14 Our series of immunohistochemical studies for mucin expression in various human tumors, including pancreatic tumors, have demonstrated that the expression of MUC1 mucin (membrane mucin) is related to an invasive proliferation of tumors and/or a poor outcome for the patient.…”

Tumor necrosis factor‐α induces the aberrant expression of mucus core protein‐2 in non‐neoplastic biliary epithelial cells via the upregulation of CDX2 in chronic cholangitis

“…Intestinal metaplasia showing goblet cells, Paneth cells, and endocrine cells, is known to occur in non‐neoplastic and neoplastic conditions in extra‐intestinal organs, such as the pancreas, stomach, and esophagus 1–4 . Intestinal metaplasia, particularly goblet cell metaplasia, is also known to develop in the diseased biliary tree in chronic cholangitis, such as hepatolithiasis 5–7 …”