Differenzielle Muzinexpression im Gastrointestinaltrakt

Zusammenfassung

Muzine zeigen im physiologischen Zustand ein gewebespezifisches Expressionsmuster. Die wichtigsten Muzingene im Gastrointestinaltrakt sind MUC2, MUC3, MUC5AC und MUC6. MUC2 und MUC3 werden vorwiegend im Darm exprimiert, MUC5AC und MUC6 im Magen.

Pathophysiologische Zustände sind durch eine aberrante Expression von gewebsunspezifischen Muzinen und/oder eine reduzierte Expression gewebsspezifischer Muzine gekennzeichnet.

Hierbei überwiegt bei entzündlichen Prozessen die Koexpression von gewebsunspezifischen Muzinen. Bei neoplastischen Veränderungen findet sich ebenfalls eine aberrante Muzinexpression. Offensichtlich sind die prognostisch günstigeren Formen mit einer hohen aberranten Expression nichtspezifischer Muzine assoziiert. Bei prognostisch ungünstigeren Neoplasien findet sich, anscheinend als Ausdruck einer fortschreitenden Entdifferenzierung, eine reduzierte Expression dieser Muzine.

Bei dieser veränderten Muzinexpression spielen nicht nur posttranskriptionelle Veränderungen eine Rolle, auch die Muzingene können hier unterschiedlich reguliert sein.

Eine modifizierte Muzinexpression lässt auf einen pathophysiologischen Zustand schließen und kann die pathohistologische Diagnostik ergänzen.

Abkürzungen: MUC: Muzingen; NTR: non-tandem repeat; TR: tandem repeat

Differential mucin expression in the gastrointestinal tract

Under physiological conditions mucins display a tissue specific expression. MUC2, MUC3, MUC5AC and MUC6 are the major mucins in the gastrointestinal tract. In the intestinal tissue MUC2 and MUC3 are the predominant mucins, whereas MUC5AC and MUC6 are the most important mucins in the stomach.

Pathophysiological conditions are characterized by an aberrant gene expression. This includes the expression of non-tissue specific mucins as well as a reduced expression of the specific mucins. During inflammation a co-expression of non-tissue specific mucins was observed. Neoplastic transformations are also associated with an aberrant mucin expression. Obviously, an increased expression of non-specific mucins is related with a more favorable prognosis, while a decreased mucin expression is indicative for an increased cellular dedifferentiation and a poor prognosis. This modified mucin expression may result from a modified gene expression as well as from modifications in the posttranscriptional processing.

A modified mucin expression reflects pathophysiological conditions and may support the pathohistological diagnosis.

Abbreviations: MUC: Mucin Gene, NTR Non-tandem Repeat, TR Tandem Repeat

Schlüsselwörter

Muzine - MUC-Gene - Gastrointestinaltrakt - gastrointestinale Tumoren

Key words

Mucins - MUC-Genes - Gastrointestinal Tract - Gastrointestinal Neoplasia

Literatur

• 1 Forstner J F, Forstner G G. Gastrointestinal mucus. Johnson LR Physiology of the gastrointestinal tract New York; Raven Press 1994: 1255-1283
• 2 Neutra M R, Forstner J F. Gastrointestinal mucus: Synthesis, secretion, and function. Johnson LR Physiology of the gastrointestinal tract New York; Raven Press 1987: 975-1009
• 3 Allen A, Bell A, Mantle M, Pearson J P. The structure and physiology of gastrointestinal mucus.  Adv Exp Med Biol. 1982;  144 115-133
• 4 Allen A, Hutton D A, Leonard A J, Pearson J P, Sellers L A. The role of mucus in the protection of the gastroduodenal mucosa.  Scand J Gastroenterol Suppl. 1986;  125 71-78
• 5 Rose M C. Mucins: Structure, function, and role in pulmonary diseases.  Am J Physiol. 1992;  263 L413-L429
• 6 Strous G J, Dekker J. Mucin-type glycoproteins.  Crit Rev Biochem Mol Biol. 1992;  27 57-92
• 7 Allen A, Leonard A. Mucus structure.  Gastroenterol Clin Biol. 1985;  9 9-12
• 8 Carlstedt I, Sheehan J K. Structure and macromolecular properties of mucus glycoproteins.  Monogr Allergy. 1988;  24 16-24
• 9 Carlstedt I, Sheehan J K. Macromolecular properties and polymeric structure of mucus glycoproteins.  Ciba Found Symp. 1984;  109 157-172
• 10 Gum J R Jr, Hicks J W, Toribara N W. et al . The human MUC2 intestinal mucin has cysteine-rich subdomains located both upstream and downstream of its central repetitive region.  J Biol Chem. 1992;  267 21 375-21 383
• 11 Bell A E, Allen A, Morris E, Rees D A. The structure of native gastric mucus gel.  Biochem Soc Trans. 1980;  8 716
• 12 Sellers L A, Allen A, Morris E R, Ross-Murphy S B. Mucus glycoprotein gels. Role of glycoprotein polymeric structure and carbohydrate side-chains in gel-formation.  Carbohydr Res. 1988;  178 93-110
• 13 Dekker J, Aelmans P H, Strous G J. The oligomeric structure of rat and human gastric mucins.  Biochem J. 1991;  277 (Pt. 2) 423-427
• 14 Gendler S J, Lancaster C A, Taylor-Papadimitriou J. et al . Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin.  J Biol Chem. 1990;  265 15 286-15 293
• 15 Pemberton L, Taylor-Papadimitriou J, Gendler S J. Antibodies to the cytoplasmic domain of the MUC1 mucin show conservation throughout mammals.  Biochem Biophys Res Commun. 1992;  185 167-175
• 16 Gum J R Jr. Human mucin glycoproteins: Varied structures predict diverse properties and specific functions.  Biochem Soc Trans. 1995;  23 795-799
• 17 Gendler S J, Spicer A P. Epithelial mucin genes.  Annu Rev Physiol. 1995;  57 607-634
• 18 Hakomori S. Aberrant glycosylation in cancer cell membranes as focused on glycolipids: overview and perspectives.  Cancer Res. 1985;  45 2405-2414
• 19 Hakomori S. Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism.  Cancer Res. 1996;  56 5309-5318
• 20 Hakomori S. Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens.  Adv Cancer Res. 1989;  52 257-331
• 21 Egea G, Franci C, Gambus G. et al . cis-Golgi resident proteins and O-glycans are abnormally compartmentalized in the RER of colon cancer cells.  J Cell Sci. 1993;  105 (Pt. 3) 819-830
• 22 Carrato C, Balague C, de Bolos C. et al . Differential apomucin expression in normal and neoplastic human gastrointestinal tissues.  Gastroenterology. 1994;  107 160-172
• 23 Bell A E, Allen A, Morris E, Rees D A. Rheological studies on native pig gastric mucus gel.  Adv Exp Med Biol. 1982;  144 97-99
• 24 Gendler S J, Burchell J M, Duhig T. et al . Cloning of partial cDNA encoding differentiation and tumor-associated mucin glycoproteins expressed by human mammary epithelium.  Proc Natl Acad Sci USA. 1987;  84 6060-6064
• 25 Gendler S J, Cohen E P, Craston A. et al . The locus of the polymorphic epithelial mucin (PEM) tumour antigen on chromosome 1q21 shows a high frequency of alteration in primary human breast tumours.  Int J Cancer. 1990;  45 431-435
• 26 Gum J R, Byrd J C, Hicks J W. et al . Molecular cloning of human intestinal mucin cDNAs. Sequence analysis and evidence for genetic polymorphism.  J Biol Chem. 1989;  264 6480-6487
• 27 Gum J R, Hicks J W, Kim Y S. Identification and characterization of the MUC2 (human intestinal mucin) gene 5’-flanking region: Promoter activity in cultured cells.  Biochem J. 1997;  325 (Pt. 1) 259-267
• 28 Gum J R Jr, Hicks J W, Toribara N W, Siddiki B, Kim Y S. Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor.  J Biol Chem. 1994;  269 2440-2446
• 29 Pigny P, Guyonnet-Duperat V, Hill A S. et al . Human mucin genes assigned to 11p15.5: identification and organization of a cluster of genes.  Genomics. 1996;  38 340-352
• 30 Fox M F, Lahbib F, Pratt W. et al . Regional localization of the intestinal mucin gene MUC3 to chromosome 7q22.  Ann Hum Genet. 1992;  56 (Pt. 4) 281-287
• 31 Gum J R, Hicks J W, Swallow D M. et al . Molecular cloning of cDNAs derived from a novel human intestinal mucin gene.  Biochem Biophys Res Commun. 1990;  171 407-415
• 32 Gum J R Jr, Ho J JL, Pratt W S. et al . MUC3 human intestinal mucin. Analysis of gene structure, the carboxyl terminus, and a novel upstream repetitive region.  J Biol Chem. 1997;  272 26 678-26 686
• 33 Porchet N, Nguyen V C, Dufosse J. et al . Molecular cloning and chromosomal localization of a novel human tracheo-bronchial mucin cDNA containing tandemly repeated sequences of 48 base pairs.  Biochem Biophys Res Commun. 1991;  175 414-422
• 34 Gross M S, Guyonnet-Duperat V, Porchet N. et al . Mucin 4 (MUC4) gene: Regional assignment (3q29) and RFLP analysis.  Ann Genet. 1992;  35 21-26
• 35 Guyonnet D uperat V, Audie J P, Debailleul V. et al . Characterization of the human mucin gene MUC5AC: A consensus cysteine-rich domain for 11p15 mucin genes?.  Biochem J. 1995;  305 (Pt. 1) 211-219
• 36 Buisine M P, Desseyn J L, Porchet N. et al . Genomic organization of the 3’-region of the human MUC5AC mucin gene: Additional evidence for a common ancestral gene for the 11p15.5 mucin gene family.  Biochem J. 1998;  332 (Pt. 3) 729-738
• 37 Ho S B, Roberton A M, Shekels L L. et al . Expression cloning of gastric mucin complementary DNA and localization of mucin gene expression.  Gastroenterology. 1995;  109 735-747
• 38 van de Bovenkamp J H, Hau C M, Strous G J. et al . Molecular cloning of human gastric mucin MUC5AC reveals conserved cysteine-rich D-domains and a putative leucine zipper motif.  Biochem Biophys Res Commun. 1998;  245 853-859
• 39 Dufosse J, Porchet N, Audie J P. et al . Degenerate 87-base-pair tandem repeats create hydrophilic/hydrophobic alternating domains in human mucin peptides mapped to 11p15.  Biochem J . 1993;  293 (Pt. 2) 329-337
• 40 Desseyn J L, Aubert J P, Van Senningen I, Porchet N, Laine A. Genomic organization of the 3’ region of the human mucin gene MUC5B.  J Biol Chem. 1997;  272 16 873-16 883
• 41 Desseyn J L, Buisine M P, Porchet N, Aubert J P, Laine A. Genomic organization of the human mucin gene MUC5B. cDNA and genomic sequences upstream of the large central exon.  J Biol Chem. 1998;  273 30 157-30 164
• 42 Desseyn J L, Guyonnet-Duperat V, Porchet N, Aubert J P, Laine A. Human mucin gene MUC5B, the 10.7-kb large central exon encodes various alternate subdomains resulting in a super-repeat. Structural evidence for a 11p15.5 gene family.  J Biol Chem. 1997;  272 3168-3178
• 43 Keates A C, Nunes D P, Afdhal N H, Troxler R F, Offner G D. Molecular cloning of a major human gall bladder mucin: complete C-terminal sequence and genomic organization of MUC5B.  Biochem J. 1997;  324 (Pt. 1) 295-303
• 44 Offner G D, Nunes D P, Keates A C, Afdhal N H, Troxler R F. The amino-terminal sequence of MUC5B contains conserved multifunctional D domains: implications for tissue-specific mucin functions.  Biochem Biophys Res Commun. 1998;  251 350-355
• 45 Toribara N W, Ho S B, Gum E. et al . The carboxyl-terminal sequence of the human secretory mucin, MUC6. Analysis of the primary amino acid sequence.  J Biol Chem. 1997;  272 16 398-16 403
• 46 Toribara N W, Roberton A M, Ho S B. et al . Human gastric mucin. Identification of a unique species by expression cloning.  J Biol Chem. 1993;  268 5879-5885
• 47 Biesbrock A R, Bobek L A, Levine M J. MUC7 gene expression and genetic polymorphism.  Glycoconj J. 1997;  14 415-422
• 48 Bobek L A, Liu J, Sait S N. et al . Structure and chromosomal localization of the human salivary mucin gene, MUC7.  Genomics. 1996;  31 277-282
• 49 Bobek L A, Tsai H, Biesbrock A R, Levine M J. Molecular cloning, sequence, and specificity of expression of the gene encoding the low molecular weight human salivary mucin (MUC7).  J Biol Chem. 1993;  268 20 563-20 569
• 50 Shankar V, Pichan P, Eddy R L Jr. et al . Chromosomal localization of a human mucin gene (MUC8) and cloning of the cDNA corresponding to the carboxy terminus.  Am J Respir Cell Mol Biol. 1997;  16 232-241
• 51 Lapensee L, Paquette Y, Bleau G. Allelic polymorphism and chromosomal localization of the human oviductin gene (MUC9).  Fertil Steril. 1997;  68 702-708
• 52 Williams S J, McGuckin M A, Gotley D C. et al . Two novel mucin genes down-regulated in colorectal cancer identified by differential display.  Cancer Res. 1999;  59 4083-4089
• 53 Allen A, Flemstrom G, Garner A, Kivilaakso E. Gastroduodenal mucosal protection.  Physiol Rev. 1993;  73 823-857
• 54 Allen A, Pearson J P, Blackburn A. et al . Pepsins and the mucus barrier in peptic ulcer disease.  Scand J Gastroenterol Suppl. 1988;  146 50-57
• 55 Van Klinken B J, Dekker J, Buller H A, Einerhand A W. Mucin gene structure and expression: Protection vs. adhesion.  Am J Physiol. 1995;  269 G613-G627
• 56 Thornton D J, Khan N, Mehrotra R. et al . Salivary mucin MG1 is comprised almost entirely of different glycosylated forms of the MUC5B gene product.  Glycobiology. 1999;  9 293-302
• 57 Liu B, Rayment S, Oppenheim F G, Troxler R F. Isolation of human salivary mucin MG2 by a novel method and characterization of its interactions with oral bacteria.  Arch Biochem Biophys. 1999;  364 286-293
• 58 Khan S H, Aguirre A, Bobek L A. In-situ hybridization localized MUC7 mucin gene expression to the mucous acinar cells of human and MUC7-transgenic mouse salivary glands.  Glycoconj J. 1998;  15 1125-1132
• 59 Bolscher J G, Groenink J, van der Kwaak J S. et al . Detection and quantification of MUC7 in submandibular, sublingual, palatine, and labial saliva by anti-peptide antiserum.  J Dent Res. 1999;  78 1362-1369
• 60 Moerk H, Scheurlen M, Al-Taie O. et al . Characterization of Barrett’s and regenerative squamous mucosa by MUC1 and MUC2 mRNA expression.  Gastroenterology. 2000;  118 A226
• 61 Labouvie C, Machado J C, Carneiro F. et al . Differential expression of mucins and trefoil peptides in native epithelium, Barrett’s metaplasia and squamous cell carcinoma of the oesophagus.  J Cancer Res Clin Oncol. 1999;  125 71-76
• 62 Chinyama C N, Marshall R E, Owen W J. et al . Expression of MUC1 and MUC2 mucin gene products in Barrett’s metaplasia, dysplasia and adenocarcinoma: An immunopathological study with clinical correlation.  Histopathology. 1999;  35 517-524
• 63 Ho S B, Shekels L L, Toribara N W. et al . Mucin gene expression in normal, preneoplastic, and neoplastic human gastric epithelium.  Cancer Res. 1995;  55 2681-2690
• 64 de Bolos C, Garrido M, Real F X. MUC6 apomucin shows a distinct normal tissue distribution that correlates with Lewis antigen expression in the human stomach.  Gastroenterology. 1995;  109 723-734
• 65 Wagner S, Enss M L, Cornberg M. et al . Morphological and molecular characterization of human gastric mucous cells in long-term primary culture.  Pflugers Arch. 1998;  436 871-881
• 66 Cornberg M, Enss M L, Makkink M K. et al . Variation of human mucin gene expression in gastric cancer cell lines and gastric mucous cell primary cultures.  Eur J Cell Biol. 1999;  78 832-841
• 67 Ho S B, Niehans G A, Lyftogt C. et al . Heterogeneity of mucin gene expression in normal and neoplastic tissues.  Cancer Res. 1993;  53 641-651
• 68 Van Den Brink G R, Tytgat K M, Van Der Hulst R W. et al . H pylori colocalises with MUC5AC in the human stomach.  Gut. 2000;  46 601-607
• 69 Byrd J C, Yan P, Sternberg L. et al . Aberrant expression of gland-type gastric mucin in the surface epithelium of Helicobacter pylori-infected patients.  Gastroenterology. 1997;  113 455-464
• 70 Byrd J C, Yunker C K, Xu Q S, Sternberg L R, Bresalier R S. Inhibition of gastric mucin synthesis by Helicobacter pylori.  Gastroenterology. 2000;  118 1072-1079
• 71 Beil W, Enss M L, Muller S. et al . Role of vacA and cagA in Helicobacter pylori inhibition of mucin synthesis in gastric mucous cells.  J Clin Microbiol. 2000;  38 2215-2218
• 72 Van Klinken B J, Van Dijken T C, Oussoren E. et al . Molecular cloning of human MUC3 cDNA reveals a novel 59 amino acid tandem repeat region.  Biochem Biophys Res Commun. 1997;  238 143-148
• 73 Buisine M P, Desreumaux P, Debailleul V. et al . Abnormalities in mucin gene expression in Crohn’s disease.  Inflamm Bowel Dis. 1999;  5 24-32
• 74 Chang S K, Dohrman A F, Basbaum C B. et al . Localization of mucin (MUC2 and MUC3) messenger RNA and peptide expression in human normal intestine and colon cancer.  Gastroenterology. 1994;  107 28-36
• 75 Weiss A A, Babyatsky M W, Ogata S, Chen A, Itzkowitz S H. Expression of MUC2 and MUC3 mRNA in human normal, malignant, and inflammatory intestinal tissues.  J Histochem Cytochem. 1996;  44 1161-1166
• 76 Bartman A E, Sanderson S J, Ewing S L. et al . Aberrant expression of MUC5AC and MUC6 gastric mucin genes in colorectal polyps.  Int J Cancer. 1999;  80 210-218
• 77 Ogata S, Uehara H, Chen A, Itzkowitz S H. Mucin gene expression in colonic tissues and cell lines.  Cancer Res. 1992;  52 5971-5978
• 78 Van Klinken B J, Dekker J, van Gool S A. et al . MUC5B is the prominent mucin in human gallbladder and is also expressed in a subset of colonic goblet cells.  Am J Physiol. 1998;  274 G871-G878
• 79 Buisine M P, Janin A, Maunoury V. et al . Aberrant expression of a human mucin gene (MUC5AC) in rectosigmoid villous adenoma.  Gastroenterology. 1996;  110 84-91
• 80 Tytgat K M, Van der Wal J W, Einerhand A W, Buller H A, Dekker J. Quantitative analysis of MUC2 synthesis in ulcerative colitis.  Biochem Biophys Res Commun. 1996;  224 397-405
• 81 Balague C, Gambus G, Carrato C. et al . Altered expression of MUC2, MUC4, and MUC5 mucin genes in pancreas tissues and cancer cell lines.  Gastroenterology. 1994;  106 1054-1061
• 82 Terada T, Ohta T, Sasaki M, Nakanuma Y, Kim Y S. Expression of MUC apomucins in normal pancreas and pancreatic tumours.  J Pathol. 1996;  180 160-165
• 83 Yonezawa S, Horinouchi M, Osako M. et al . Gene expression of gastric type mucin (MUC5AC) in pancreatic tumors: Its relationship with the biological behavior of the tumor.  Pathol Int. 1999;  49 45-54
• 84 Balague C, Audie J P, Porchet N, Real F X. In situ hybridization shows distinct patterns of mucin gene expression in normal, benign, and malignant pancreas tissues.  Gastroenterology. 1995;  109 953-964
• 85 Hanski C, Hofmeier M, Schmitt-Graff A. et al . Overexpression or ectopic expression of MUC2 is the common property of mucinous carcinomas of the colon, pancreas, breast, and ovary.  J Pathol. 1997;  182 385-391
• 86 Yonezawa S, Sueyoshi K, Nomoto M. et al . MUC2 gene expression is found in noninvasive tumors but not in invasive tumors of the pancreas and liver: Its close relationship with prognosis of the patients.  Hum Pathol. 1997;  28 344-352
• 87 Vandenhaute B, Buisine M P, Debailleul V. et al . Mucin gene expression in biliary epithelial cells.  J Hepatol. 1997;  27 1057-1066
• 88 Bartman A E, Buisine M P, Aubert J P. et al . The MUC6 secretory mucin gene is expressed in a wide variety of epithelial tissues.  J Pathol. 1998;  186 398-405
• 89 Ho S B, Shekels L L, Toribara N W. et al . Altered mucin core peptide expression in acute and chronic cholezystitis.  Dig Dis Sci. 2000;  45 1061-1071
• 90 Sasaki M, Nakanuma Y. Frequent expression of MUC1 apomucin on biliary epithelial cells of damaged small bile ducts in primary biliary cirrhosis and chronic viral hepatitis: An immunohistochemical study.  Hepatology. 1996;  23 1313-1317

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