Mucins are high molecular weight glycoprotein components of mucus, which protect and lubricate the epithelial surfaces of the respiratory, gastrointestinal and reproductive tracts in the body. In humans, to date, about six secreted and 14 membrane-tethered mucins have been reported based on cloned complementary DNA (cDNA) sequences [1, 2].
MUC2 is the major secreted mucin in the large and small intestine with an O-linked carbohydrate. MUC2 presents in normal gastrointestinal secretion products and epithelia, and in some tumors . Alteration of MUC2 expression may contribute to change in growth regulation, immune recognition, cellular adhesion, carcinoma-host and other cellular interactions, which may influence the invasive and metastatic capabilities of the cancer [4, 5]. The aberrant expression of MUC2 is together with altered expression of MUC5AC and MUC6 in intestinal metaplasia during the process of gastric carcinogenesis. And the MUC2 expression pattern is a reliable marker of intestinal metaplasia associated H. pylori infected individuals . The increased MUC2 expression in intestinal metaplasia in the neighborhood of the carcinomas may play an important role in gastric carcinomas or IPMN [7, 8]. It has been recently suggested that mucin genes have a regulatory role for their products during cell proliferation and differentiation, and this leads to carcinogenesis when these gene products are expressed inappropriately in the pathogenesis of breast cancer, gastric carcinomas, etc. [1, 9].
Human normal bile ducts do not show MUC2, and MUC2 mRNA was detectable in the normal cholangiocytes. But the presence of MUC2 protein was not demonstrable by immunohistochemical staining cholangiocarcinoma [10, 11]. MUC2 expression were observed in 42.0% of 193 extrahepatic bile duct carcinomas . The conventional intrahepatic cholangiocarcinoma (ICC) frequently expressed MUC5AC, but no MUC2, in carcinoma cells. Therefore, the expression of MUC2 seems to be a specific feature of mucinous ICC and Intraductal papillary neoplasia of the liver . Colonic epithelial metaplasia resembling regenerating colonic epithelia and/or tubular adenoma of the colon also occur in hyperplastic and dysplastic biliary lining epithelia in chronic biliary disease and is positive for MUC2 and CK20 [14, 15]. However, the results regarding correlations of MUC2 expression in cancer are contradictory .
Given that the aberrant expression of MUC2, it is conceivable that MUC2 may be also involved in the development of cellular differentiation in Hepatocellular Carcinoma . Relatively little is known, however, about the mechanisms responsible for regulation of MUC2 expression in HCC. MUC2 gene regulation mechanism disclosed that DNA methylation and histone modification in the 5’ flanking region of the MUC2 promoter may play an important role . MUC2 are highly submitted to DNA methylation and histone modifications, and MUC2 repression by cell-specified methylation is controlled by DNA methyltransferase 1 (DNMT1) and dramatically impairs their activation by the transcription factor Sp1 in epithelial cancer cells [18, 19]. MUC2 expression in gastric cells is regulated by promoter methylation with two specific CpG sites . And the low methylation status of MUC2 gene plays a predominant role in high level MUC2 expression in mucinous colorectal cancer . The histone H3 modification could play an important role in MUC2 gene expression, possibly affecting DNA methylation in pancreatic neoplasm . It implied that the promoter methylation of MUC2 could play a particularly important regulatory role for MUC2 expression in carcinogenesis.
So far the few studies conducted focused on MUC2 methylation and no data are available regarding MUC2 in HCC. In this study, we examined the expression of MUC2 with respect to the promoter methylation in HCC.