The Biological Role of Oligosaccharide Chains in Digestive Diseases
	1. Glycolipids and digestive diseases Glycolipids are classified as glycerolipids and sphingolipids according to difference in the lipid portion. In relation to digestive diseases, these molecules are assumed to play a role as adhesion receptors for cholera toxin, and their alteration caused by malignant diseases play a role as tumor antigens, i.e. as tumor markers. For example, CA19-9, which is a marker of malignant diseases such as pancreatic and colon cancer, is now clinically used for diagnosis many patients. Moreover, glycolipids serve as attachment receptors not only for microorganisms but also for adhesion molecules such as selectin. For instance, the lectin-like protein, adhesin, at the end of microvilli of Escherichia coli strains is known to recognize these glycoreceptors of host cell membrane. Recently, it has come to be assumed that sulfatide (3'-sulfogalactosyl ceramide) among the acidic glycosphingolipids, abundant in the apical surface of epithelium, serves as an attachment receptor in Helicobacter pylori infection, leading to peptic ulcer and gastric carcinoma. In addition, these acidic glycosphingolipids, which are produced and secreted in the epithelium, play a role in mucosal protection from injuries frequently induced by various factors. 2. Mucin and digestive diseases Mucin plays a role in cellular protection and the many sugars on the extended structure are well exposed, potentially leading to multiple interactions with, for instance, leukocytes, bacteria or viruses that contain receptors for the sugar residues of mucins, leading to selective adhesion. In humans, so far nine epithelial mucin genes have been identified and designated MUC1-4, MUC5B, MUC5A/C and MUC6-8. Consequently, mucin expression is known to be qualitatively and/or quantitatively abnormal in a number of diseases. For instance, normal mucosa of the stomach was characterized by the expression of MUC1, MUC5A/C, MUC6 mRNA and immunoreactive protein. In contrast, high levels of MUC2, MUC3 mucin mRNA and immunoreactive protein were found in specimens with intestinal metaplasia. Gastric cancer exhibited markedly altered secretory mucin mRNA levels compared with adjacent normal mucosa, with decreased levels of MUC5 and MUC6 mRNA and increased levels of MUC3 and MUC4 mRNA. High levels of MUC2 and MUC3 mRNA and protein are detectable in the small intestine, and MUC2 is the most abundant colonic mucin. Recently, it was reported that inflammatory bowel disease has an abnormal mucin gene. It is possible that alterations in the length of the tandem repeats in MUC2 predisposes an individual toword the occurrence of ulcerative colitis. It is possible that altered MUC2 alleles that fail to polymerize adequately are a factor genetically predisposing individuals to diseases such as ulcerative colitis.
Designation Tandem repeat amino acid sequence (No. of umiino acid) Source Chromosomal location MUC1 PDTRPAPGSTAPPAHGVTSA(20) Mammary Pancrcatic 1q21 MUC2 PTTTPPITTTTTVTPTPTPTGTQT(23) Intestinal Tracheobronchial 11p15 MUC3 HSTPSFTSSITTTETTS(17) Intestinal Gallbladder 7q22 MUC4 TSSASTGHATPLPVTD(16) Colon Tracheobronchial 3p29 MUC5AC TTSTTSAP(8) Gastric Tracheobronchial 11p15 MUC5B SSTPGTAHTLTMLTTTATTPTATGSTATP(290) Tracheobronchial Salivary 11p15 MUC6 omitted S(30) T(52) P(25) (total169) Gastric Gallbladder 11p15 MUC7 TTAAPPTPSATTPAPPSSSAPG(22) Salivary 4 MUC8 TSCPRPLQEGTPGSRAAHALSRRGHRVHELPTSSPGGDTGF(41) Tracheobronchial Tandem repeat aminoacids of MUC6 are omitted and main amino acids and their number are shown. Reference: Gum : Mucins: their structure and biology. Biochem Soc Trans 23,1995.
	3. Mucin and metastatic tumor Glycoproteins may be involved in several stages of metastasis, including cell growth, motility during invasion, and adherence of metastatic cells to endothelia and the extracellular matrix. Mucins are the major secreted glycoproteins of the colon, and those changes could alter the biological behavior of tumors. It has been suggested that stepwise changes in glycosylation parallel steps in the metastatic cascade. In a series of experiments in animal models, the cell line LIM-6, which was selected for its high metastatic capacity, produces more than twice the amount of mucin produced by the parental cell line of human colon adenocarcinoma origin, LS174T. Inhibition of mucin glycosylation by aryglycoside benzyl-alpha-N-acetylgalactosamine greatly reduced liver colonization after splenic injection of the cells. Similar results were found in a nude mouse model with another glycoprotein that is secreted by colon cancer cells: carcinoembryonic antigen (CEA). The more CEA secreted, the greater the number of colonies found in the liver. CEA may be involved in intercellular recognition and binding, and may facilitate attachment of cancer cells to sites of metastasis. Similarly, it was found that high molecular sialoglycoprotein was more prominent in metastasis.
	Hiroyuki Osawa (Department of Gastroenterology, Jichi Medical School)
	References (1) Klinken, J, Buller, HA, Einerhand, AWC : Mucin gene structure and expression: protection vs. adhesion. Am. J. Physiol. 269, G613-G627,1995 (2) Niv, Y : Mucin and colorectal cancer metastasis. Am. J.Gastroenterol. 89, 665-669, 1994
Dec. 15, 1999