• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of gutGutVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
Gut. Sep 2000; 47(3): 349–356.
PMCID: PMC1728024

Role of fucosyltransferases in the association between apomucin and Lewis antigen expression in normal and malignant gastric epithelium

Abstract

BACKGROUND—In normal gastric epithelium, MUC5AC is detected in superficial epithelium associated with Lewis type 1 antigens and MUC6 is detected in antral glands with Lewis type 2. Therefore, the stomach constitutes an excellent model to examine the role of glycosyltransferases in determining the specificity of apomucin glycosylation.
AIMS—To determine the molecular basis of this association and to examine changes in expression of gastric and intestinal apomucins and their association with Lewis antigens during the gastric carcinogenesis process.
METHODS—Fucosyltransferase (FUT1, FUT2, FUT3) and mucin (MUC5AC, MUC6) transcripts were detected using reverse transcription-polymerase chain reaction. Apomucin (MUC2, MUC4, MUC5AC, MUC6) and Lewis antigen (types 1 and 2) expression were analysed using single and double immunohistochemistry and in situ hybridisation.
RESULTS—In the normal stomach, FUT1 is exclusively detected associated with MUC6; FUT2 is only detected when MUC5AC is present. This co-regulation is lost in gastric tumours, as is differential expression of MUC5AC and MUC6 in normal gastric epithelial cells. In gastric tumours, especially those with the intestinal phenotype, MUC2 and MUC4 genes are upregulated, and gastric-type and intestinal-type mucins are coexpressed. These changes are early events in the gastric carcinogenesis process, as they are detected in intestinal metaplasia.
CONCLUSIONS—The glycosylation pattern found in normal gastric epithelium is dictated by the specific set of fucosyltranferases expressed by the cells rather than by the apomucin sequence. The development of intestinal metaplasia and gastric cancer is associated with the appearance of cellular phenotypes that are absent from normal epithelium.


Keywords: fucosyltransferases; gastric carcinogenesis; gastric mucins; Lewis antigens

Full Text

The Full Text of this article is available as a PDF (203K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Gendler SJ, Burchell JM, Duhig T, Lamport D, White R, Parker M, Taylor-Papadimitriou J. Cloning of partial cDNA encoding differentiation and tumor-associated mucin glycoproteins expressed by human mammary epithelium. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6060–6064. [PMC free article] [PubMed]
  • Lan MS, Batra SK, Qi WN, Metzgar RS, Hollingsworth MA. Cloning and sequencing of a human pancreatic tumor mucin cDNA. J Biol Chem. 1990 Sep 5;265(25):15294–15299. [PubMed]
  • Gum JR, Jr, Hicks JW, Toribara NW, Siddiki B, Kim YS. 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 Jan 28;269(4):2440–2446. [PubMed]
  • Gum JR, Byrd JC, Hicks JW, Toribara NW, Lamport DT, Kim YS. Molecular cloning of human intestinal mucin cDNAs. Sequence analysis and evidence for genetic polymorphism. J Biol Chem. 1989 Apr 15;264(11):6480–6487. [PubMed]
  • Gum JR, Hicks JW, Swallow DM, Lagace RL, Byrd JC, Lamport DT, Siddiki B, Kim YS. Molecular cloning of cDNAs derived from a novel human intestinal mucin gene. Biochem Biophys Res Commun. 1990 Aug 31;171(1):407–415. [PubMed]
  • Porchet N, Nguyen VC, Dufosse J, Audie JP, Guyonnet-Duperat V, Gross MS, Denis C, Degand P, Bernheim A, Aubert JP. 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 Mar 15;175(2):414–422. [PubMed]
  • Dufosse J, Porchet N, Audie JP, Guyonnet Duperat V, Laine A, Van-Seuningen I, Marrakchi S, Degand P, Aubert JP. Degenerate 87-base-pair tandem repeats create hydrophilic/hydrophobic alternating domains in human mucin peptides mapped to 11p15. Biochem J. 1993 Jul 15;293(Pt 2):329–337. [PMC free article] [PubMed]
  • Crepin M, Porchet N, Aubert JP, Degand P. Diversity of the peptide moiety of human airway mucins. Biorheology. 1990;27(3-4):471–484. [PubMed]
  • Toribara NW, Roberton AM, Ho SB, Kuo WL, Gum E, Hicks JW, Gum JR, Jr, Byrd JC, Siddiki B, Kim YS. Human gastric mucin. Identification of a unique species by expression cloning. J Biol Chem. 1993 Mar 15;268(8):5879–5885. [PubMed]
  • Bobek LA, Tsai H, Biesbrock AR, Levine MJ. Molecular cloning, sequence, and specificity of expression of the gene encoding the low molecular weight human salivary mucin (MUC7). J Biol Chem. 1993 Sep 25;268(27):20563–20569. [PubMed]
  • Carrato C, Balague C, de Bolos C, Gonzalez E, Gambus G, Planas J, Perini JM, Andreu D, Real FX. Differential apomucin expression in normal and neoplastic human gastrointestinal tissues. Gastroenterology. 1994 Jul;107(1):160–172. [PubMed]
  • Audie JP, Janin A, Porchet N, Copin MC, Gosselin B, Aubert JP. Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. J Histochem Cytochem. 1993 Oct;41(10):1479–1485. [PubMed]
  • De Bolós C, Garrido M, Real FX. MUC6 apomucin shows a distinct normal tissue distribution that correlates with Lewis antigen expression in the human stomach. Gastroenterology. 1995 Sep;109(3):723–734. [PubMed]
  • Kelly RJ, Rouquier S, Giorgi D, Lennon GG, Lowe JB. Sequence and expression of a candidate for the human Secretor blood group alpha(1,2)fucosyltransferase gene (FUT2). Homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J Biol Chem. 1995 Mar 3;270(9):4640–4649. [PubMed]
  • Cameron HS, Szczepaniak D, Weston BW. Expression of human chromosome 19p alpha(1,3)-fucosyltransferase genes in normal tissues. Alternative splicing, polyadenylation, and isoforms. J Biol Chem. 1995 Aug 25;270(34):20112–20122. [PubMed]
  • Kelly RJ, Ernst LK, Larsen RD, Bryant JG, Robinson JS, Lowe JB. Molecular basis for H blood group deficiency in Bombay (Oh) and para-Bombay individuals. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5843–5847. [PMC free article] [PubMed]
  • Torrado J, Correa P, Ruiz B, Bernardi P, Zavala D, Bara J. Lewis antigen alterations in gastric cancer precursors. Gastroenterology. 1992 Feb;102(2):424–430. [PubMed]
  • Murata K, Egami H, Shibata Y, Sakamoto K, Misumi A, Ogawa M. Expression of blood group-related antigens, ABH, Lewis(a), Lewis(b), Lewis(x), Lewis(y), CA19-9, and CSLEX1 in early cancer, intestinal metaplasia, and uninvolved mucosa of the stomach. Am J Clin Pathol. 1992 Jul;98(1):67–75. [PubMed]
  • Ura H, Denno R, Hirata K, Yamaguchi K, Yasoshima T, Shishido T. Close correlation between increased sialyl-Lewisx expression and metastasis in human gastric carcinoma. World J Surg. 1997 Sep;21(7):773–776. [PubMed]
  • Ho SB, Shekels LL, Toribara NW, Kim YS, Lyftogt C, Cherwitz DL, Niehans GA. Mucin gene expression in normal, preneoplastic, and neoplastic human gastric epithelium. Cancer Res. 1995 Jun 15;55(12):2681–2690. [PubMed]
  • Reis CA, David L, Nielsen PA, Clausen H, Mirgorodskaya K, Roepstorff P, Sobrinho-Simões M. Immunohistochemical study of MUC5AC expression in human gastric carcinomas using a novel monoclonal antibody. Int J Cancer. 1997 Feb 20;74(1):112–121. [PubMed]
  • Sakamoto J, Furukawa K, Cordon-Cardo C, Yin BW, Rettig WJ, Oettgen HF, Old LJ, Lloyd KO. Expression of Lewisa, Lewisb, X, and Y blood group antigens in human colonic tumors and normal tissue and in human tumor-derived cell lines. Cancer Res. 1986 Mar;46(3):1553–1561. [PubMed]
  • Gambús G, de Bolós C, Andreu D, Francí C, Egea G, Real FX. Detection of the MUC2 apomucin tandem repeat with a mouse monoclonal antibody. Gastroenterology. 1993 Jan;104(1):93–102. [PubMed]
  • Hovenberg HW, Davies JR, Carlstedt I. Different mucins are produced by the surface epithelium and the submucosa in human trachea: identification of MUC5AC as a major mucin from the goblet cells. Biochem J. 1996 Aug 15;318(Pt 1):319–324. [PMC free article] [PubMed]
  • Egea G, Francí C, Gambús G, Lesuffleur T, Zweibaum A, Real FX. cis-Golgi resident proteins and O-glycans are abnormally compartmentalized in the RER of colon cancer cells. J Cell Sci. 1993 Jul;105(Pt 3):819–830. [PubMed]
  • Tytgat KM, Büller HA, Opdam FJ, Kim YS, Einerhand AW, Dekker J. Biosynthesis of human colonic mucin: Muc2 is the prominent secretory mucin. Gastroenterology. 1994 Nov;107(5):1352–1363. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Berrozpe G, Schaeffer J, Peinado MA, Real FX, Perucho M. Comparative analysis of mutations in the p53 and K-ras genes in pancreatic cancer. Int J Cancer. 1994 Jul 15;58(2):185–191. [PubMed]
  • Hanukoglu I, Tanese N, Fuchs E. Complementary DNA sequence of a human cytoplasmic actin. Interspecies divergence of 3' non-coding regions. J Mol Biol. 1983 Feb 5;163(4):673–678. [PubMed]
  • Lesuffleur T, Roche F, Hill AS, Lacasa M, Fox M, Swallow DM, Zweibaum A, Real FX. Characterization of a mucin cDNA clone isolated from HT-29 mucus-secreting cells. The 3' end of MUC5AC? J Biol Chem. 1995 Jun 9;270(23):13665–13673. [PubMed]
  • Laurén P. Histogenesis of intestinal and diffuse types of gastric carcinoma. Scand J Gastroenterol Suppl. 1991;180:160–164. [PubMed]
  • Kitagawa H, Paulson JC. Differential expression of five sialyltransferase genes in human tissues. J Biol Chem. 1994 Jul 8;269(27):17872–17878. [PubMed]
  • Koda Y, Soejima M, Kimura H. Structure and expression of H-type GDP-L-fucose:beta-D-galactoside 2-alpha-L-fucosyltransferase gene (FUT1). Two transcription start sites and alternative splicing generate several forms of FUT1 mRNA. J Biol Chem. 1997 Mar 14;272(11):7501–7505. [PubMed]
  • Koda Y, Soejima M, Kimura H. Changing transcription start sites in H-type alpha(1,2)fucosyltransferase gene (FUT1) during differentiation of the human erythroid lineage. Eur J Biochem. 1998 Sep 1;256(2):379–387. [PubMed]
  • Gum JR, Hicks JW, Kim YS. Identification and characterization of the MUC2 (human intestinal mucin) gene 5'-flanking region: promoter activity in cultured cells. Biochem J. 1997 Jul 1;325(Pt 1):259–267. [PMC free article] [PubMed]
  • Li D, Gallup M, Fan N, Szymkowski DE, Basbaum CB. Cloning of the amino-terminal and 5'-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts. J Biol Chem. 1998 Mar 20;273(12):6812–6820. [PubMed]
  • Lesuffleur T, Porchet N, Aubert JP, Swallow D, Gum JR, Kim YS, Real FX, Zweibaum A. Differential expression of the human mucin genes MUC1 to MUC5 in relation to growth and differentiation of different mucus-secreting HT-29 cell subpopulations. J Cell Sci. 1993 Nov;106(Pt 3):771–783. [PubMed]
  • Reis CA, David L, Correa P, Carneiro F, de Bolós C, Garcia E, Mandel U, Clausen H, Sobrinho-Simões M. Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression. Cancer Res. 1999 Mar 1;59(5):1003–1007. [PubMed]
  • Semba S, Yokozaki H, Yamamoto S, Yasui W, Tahara E. Microsatellite instability in precancerous lesions and adenocarcinomas of the stomach. Cancer. 1996 Apr 15;77(8 Suppl):1620–1627. [PubMed]
  • Ottini L, Palli D, Falchetti M, D'Amico C, Amorosi A, Saieva C, Calzolari A, Cimoli F, Tatarelli C, De Marchis L, et al. Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany. Cancer Res. 1997 Oct 15;57(20):4523–4529. [PubMed]
  • Borén T, Falk P, Roth KA, Larson G, Normark S. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science. 1993 Dec 17;262(5141):1892–1895. [PubMed]
  • Mentis A, Blackwell CC, Weir DM, Spiliadis C, Dailianas A, Skandalis N. ABO blood group, secretor status and detection of Helicobacter pylori among patients with gastric or duodenal ulcers. Epidemiol Infect. 1991 Apr;106(2):221–229. [PMC free article] [PubMed]
  • Byrd JC, Yan P, Sternberg L, Yunker CK, Scheiman JM, Bresalier RS. Aberrant expression of gland-type gastric mucin in the surface epithelium of Helicobacter pylori-infected patients. Gastroenterology. 1997 Aug;113(2):455–464. [PubMed]
  • Bry L, Falk PG, Midtvedt T, Gordon JI. A model of host-microbial interactions in an open mammalian ecosystem. Science. 1996 Sep 6;273(5280):1380–1383. [PubMed]
  • Falk PG, Bry L, Holgersson J, Gordon JI. Expression of a human alpha-1,3/4-fucosyltransferase in the pit cell lineage of FVB/N mouse stomach results in production of Leb-containing glycoconjugates: a potential transgenic mouse model for studying Helicobacter pylori infection. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1515–1519. [PMC free article] [PubMed]

Figures and Tables

Figure 1
Mucin and fucosyltransferase mRNA expression in gastric mucosa scrapings detected by RT-PCR (S, superficial epithelium; G, deep glands). MUC6 and FUT1 were detected only in the deep gland scrapings. MUC5AC and FUT2 were detected in both superficial epithelium ...
Figure 2
Mucin expression in gastric tumours. (A) MUC4 detected by immunohistochemistry in an intestinal-type tumour. (B) MUC4 expression by in situ hybridisation in a diffuse-type tumour (original magnification: A ×200; B ×100). (C) Coexpression ...
Figure 3
Gastric cancers contain cells displaying abnormal patterns of apomucin/Lewis antigen coexpression. (A) Double labelling immunohistochemical detection of MUC5AC (blue) and MUC6 expression (light brown) cells. Doubly labelled cells display a dark brown ...
Figure 4
RT-PCR analysis of fucosyltransferase (FUT1 and FUT2) and mucin (MUC5AC and MUC6) transcripts in two gastric tumours (A and B). There was no association between the presence of MUC5AC and MUC6, and FUT2 and FUT1 transcripts, respectively.
Figure 5
Expression of apomucins and Lewis antigens in intestinal metaplasia. Double labelling immunofluorescence detection of: (A) MUC2 (green) and MUC6 (red); (B) MUC4 (green) and Lewis b (red); (C) MUC5AC (green) and Lewis y (red). In incomplete intestinal ...

Articles from Gut are provided here courtesy of BMJ Group

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...