Skip to main content
SpringerLink
Log in

Regulation of glycosyltransferases and Lewis antigens expression by IL-1β and IL-6 in human gastric cancer cells

  • Published:
Glycoconjugate Journal Aims and scope Submit manuscript

Abstract

Inflammation of stomach mucosa has been postulated as initiator of gastric carcinogenesis and the presence of pro-inflammatory cytokines can regulate specific genes involved in this process. The cellular expression pattern of glycosyltransferases and Lewis antigens detected in the normal mucosa changed during the neoplassic transformation. The aim of this work was to determine the regulation of specific fucosyltransferases and sialyltransferases by IL-1β and IL-6 pro-inflammatory cytokines in MKN45 gastric cancer cells. IL-1β induced significant increases in the mRNA levels of FUT1, FUT2 and FUT4, and decreases of FUT3 and FUT5. In IL-6 treatments, enhanced FUT1 and lower FUT3 and FUT5 mRNA expression were detected. No substantial changes were observed in the levels of ST3GalIII and ST3GalIV. The activation of FUT1, FUT2 and FUT4 by IL-1β is through the NF-κB pathway and the down-regulation of FUT3 and FUT5 by IL-6 is through the gp130/STAT-3 pathway, since they are inhibited specifically by panepoxydone and AG490, respectively. The levels of Lewis antigens after IL-1β or IL-6 stimulation decreased for sialyl-Lewis x, and no significant differences were found in the rest of the Lewis antigens analyzed, as it was also observed in subcutaneous mice tumors from MKN45 cells treated with IL-1β or IL-6. In addition, in 61 human intestinal-type gastric tumors, sialyl-Lewis x was highly detected in samples from patients that developed metastasis. These results indicate that the expression of the fucosyltransferases involved in the synthesis of Lewis antigens in gastric cancer cells can be specifically modulated by IL-1β and IL-6 inflammatory cytokines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Narimatsu, H.: Recent progress in molecular cloning of glycosyltransferase genes of eukaryotes. Microbiol. Immunol. 38, 489–504 (1994)

    PubMed  CAS  Google Scholar 

  2. Hakomori, S.: Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv. Cancer Res. 52, 257–331 (1989)

    Article  PubMed  CAS  Google Scholar 

  3. Henry, S., Oriol, R., Samuelsson, B.: Lewis histo-blood group system and associated secretory phenotypes. Vox Sang. 69, 166–182 (1995)

    Article  PubMed  CAS  Google Scholar 

  4. Oriol, R.: Tissular expression of ABH and Lewis antigens in humans and animals: expected value of different animal models in the study of ABO-incompatible organ transplants. Transplant. Proc. 19, 4416–4420 (1987)

    PubMed  CAS  Google Scholar 

  5. Lopez-Ferrer, A., de Bolos, C., Barranco, C., Garrido, M., Isern, J., Carlsted, I., Reis, C.A., Torrado, J., Real, F.X., et al.: Role of fucosyltransferases in the association between apomucin and Lewis antigen expression in normal and malignant gastric epithelium. Gut 47, 349–356 (2000)

    Article  PubMed  CAS  Google Scholar 

  6. de Bolos, C., Real, F.X., Lopez-Ferrer, A.: Regulation of mucin and glycoconjugate expression: from normal epithelium to gastric tumors. Front. Biosci. 6, D1256–D1263 (2001)

    Article  PubMed  Google Scholar 

  7. Gretschel, S., Haensch, W., Schlag, P.M., Kemmner, W.: Clinical relevance of sialyltransferases ST6GAL-I and ST3GAL-III in gastric cancer. Oncology 65, 139–145 (2003)

    Article  PubMed  CAS  Google Scholar 

  8. Petretti, T., Schulze, B., Schlag, P.M., Kemmner, W.: Altered mRNA expression of glycosyltransferases in human gastric carcinomas. Biochim. Biophys. Acta 1428, 209–218 (1999)

    PubMed  CAS  Google Scholar 

  9. Aplin, J.D.: Adhesion molecules in implantation. Rev. Reprod. 2, 84–93 (1997)

    Article  PubMed  CAS  Google Scholar 

  10. Kudo, T., Kaneko, M., Iwasaki, H., Togayachi, A., Nishihara, S., Abe, K., Narimatsu, H.: Normal embryonic and germ cell development in mice lacking alpha 1, 3-fucosyltransferase IX (Fut9) which show disappearance of stage-specific embryonic antigen 1. Mol. Cell. Biol. 24(42), 21–4228 (2004)

    Google Scholar 

  11. Le Pendu, J., Marionneau, S., Cailleau-Thomas, A., Rocher, J., Moullac-Vaidye, B., Clement, M.: ABH and Lewis histo-blood group antigens in cancer. APMIS 109, 9–31 (2001)

    Article  PubMed  Google Scholar 

  12. Le Pendu, J.: Histo-blood group antigen and human milk oligosaccharides: genetic polymorphism and risk of infectious diseases. Adv. Exp. Med. Biol. 554, 135–143 (2004)

    PubMed  Google Scholar 

  13. Azevedo, M., Eriksson, S., Mendes, N., Serpa, J., Figuereido, C., Resende, L.P., Ruvoen-Clouet, N., Haas, R., Boren, T., Le Pendu, J., Devid, L.: Infection by Helicobacter pylori expressing the BabA adhesin is influenced by the secretor phenotype. J. Pathol. 215, 308–316 (2008)

    Article  PubMed  CAS  Google Scholar 

  14. Mahdavi, J., Sonden, B., Hurtig, M., Olfat, F.O., Forsberg, L., Roche, N., Angstrom, J., Larsson, T., Teneberg, S., Karlsson, K.A., Altraja, S., Wadstrom, T., Kersulyte, D., Berg, D.E., Dubois, A., Petersson, C., Magnusson, K.E., Norberg, T., Lindh, F., Lundskog, B.B., Arnqvist, A., Hammarstrom, L., Boren, T.: Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 297, 573–578 (2002)

    Article  PubMed  CAS  Google Scholar 

  15. Ashizawa, T., Aoki, T., Yamazaki, T., Katayanagi, S., Shimizu, H., Koyanagi, Y.: The clinical significance of sialyl Lewis antigen expression in the spread of gastric cancer. Flow cytometric DNA analysis. J. Exp. Clin. Cancer Res. 22, 91–98 (2003)

    PubMed  CAS  Google Scholar 

  16. Sumikura, S., Ishigami, S., Natsugoe, S., Miyazono, F., Tokuda, K., Nakajo, A., Okumura, H., Matsumoto, M., Hokita, S., Aikou, T.: Disseminated cancer cells in the blood and expression of sialylated antigen in gastric cancer. Cancer Lett. 200, 77–83 (2003)

    Article  PubMed  CAS  Google Scholar 

  17. Tatsumi, M., Watanabe, A., Sawada, H., Yamada, Y., Shino, Y., Nakano, H.: Immunohistochemical expression of the sialyl Lewis x antigen on gastric cancer cells correlates with the presence of liver metastasis. Clin. Exp. Metastasis 16, 743–750 (1998)

    Article  PubMed  CAS  Google Scholar 

  18. 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. 21, 773–776 (1997)

    Article  PubMed  CAS  Google Scholar 

  19. Kannagi, R., Izawa, M., Koike, T., Miyazaki, K., Kimura, N.: Carbohydrate-mediated cell adhesion in cancer metastasis and angiogenesis. Cancer Sci. 95, 377–384 (2004)

    Article  PubMed  CAS  Google Scholar 

  20. Crabtree, J.E., Shallcross, T.M., Heatley, R.V., Wyatt, J.I.: Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut 32, 1473–1477 (1991)

    Article  PubMed  CAS  Google Scholar 

  21. Furukawa, K., Takahashi, T., Arai, F., Matsushima, K., Asakura, H.: Enhanced mucosal expression of interleukin-6 mRNA but not of interleukin-8 mRNA at the margin of gastric ulcer in Helicobacter pylori-positive gastritis. J. Gastroenterol. 33, 625–633 (1998)

    Article  PubMed  CAS  Google Scholar 

  22. Machado, J.C., Figueiredo, C., Canedo, P., Pharoah, P., Carvalho, R., Nabais, S., Castro, A.C., Campos, M.L., Van Doorn, L.J., Caldas, C., Seruca, R., Carneiro, F., Sobrinho-Simoes, M.: A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 125, 364–371 (2003)

    Article  PubMed  CAS  Google Scholar 

  23. Noach, L.A., Bosma, N.B., Jansen, J., Hoek, F.J., van Deventer, S.J., Tytgat, G.N.: Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection. Scand. J. Gastroenterol. 29, 425–429 (1994)

    Article  PubMed  CAS  Google Scholar 

  24. Mejias-Luque, R., Linden, S.K., Garrido, M., Tye, H., Najdovska, M., Jenkins, B.J., Iglesias, M., Ernst, M., de Bolos, C.: Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors. Oncogene 12, 1753–1762 (2010)

    Article  Google Scholar 

  25. Mejias-Luque, R., Peiro, S., Vincent, A., Van Seuningen, I., de Bolos, C.: IL-6 induces MUC4 expression through gp130/STAT3 pathway in gastric cancer cell lines. Biochim. Biophys. Acta 1783, 1728–1736 (2008)

    Article  PubMed  CAS  Google Scholar 

  26. Sakamoto, J., Furukawa, K., Cordon-Cardo, C., Yin, B.W., Rettig, W.J., Oettgen, H., Old, L.J., Lloyd, K.O.: 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. 46, 1553–1561 (1986)

    PubMed  CAS  Google Scholar 

  27. Rouger, P., Gane, P., Salmon, C.: Tissue distribution of H, Lewis and P antigens as shown by a panel of 18 monoclonal antibodies. Rev Fr Transfus. Immunohematol 30, 699–708 (1987)

    Article  PubMed  CAS  Google Scholar 

  28. 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 109, 723–734 (1995)

    Article  PubMed  Google Scholar 

  29. Fukushima, K., Hirota, M., Terasaki, P.I., Wakisaka, A., Togashi, H., Chia, D., Suyama, N., Fukushi, Y., Nudelman, E., Hakomori, S.: Characterization of sialosylated Lewisx as a new tumor-associated antigen. Cancer Res. 44, 5279–5285 (1984)

    PubMed  CAS  Google Scholar 

  30. Higai, K., Ishihara, S., Matsumoto, K.: NFkappaB-p65 dependent transcriptional regulation of glycosyltransferases in human colon adenocarcinoma HT-29 by stimulation with tumor necrosis factor alpha. Biol. Pharm. Bull. 29, 2372–2377 (2006)

    Article  PubMed  CAS  Google Scholar 

  31. Mayer, B., Funke, I., Johnson, J.P.: High expression of a Lewis(x)-related epitope in gastric carcinomas indicates metastatic potential and poor prognosis. Gastroenterology 111, 1433–1446 (1996)

    Article  PubMed  CAS  Google Scholar 

  32. Nakagoe, T., Sawai, T., Tsuji, T., Jibiki, M.A., Nanashima, A., Yamaguchi, H., Yasutake, T., Ayabe, H., Arisawa, K., Ishikawa, H.: Difference in prognostic value between sialyl Lewis(a) and sialyl Lewis(x) antigen levels in the preoperative serum of gastric cancer patients. J. Clin. Gastroenterol. 34, 408–415 (2002)

    Article  PubMed  CAS  Google Scholar 

  33. Kukowska-Latallo, J.F., Larsen, R.D., Nair, R.P., Lowe, J.B.: A cloned human cDNA determines expression of a mouse stage-specific embryonic antigen and the Lewis blood group alpha(1, 3/1, 4)fucosyltransferase. Genes Dev. 4, 1288–1303 (1990)

    Article  PubMed  CAS  Google Scholar 

  34. Weston, B.W., Smith, P.L., Kelly, R.J., Lowe, J.B.: Molecular cloning of a fourth member of a human alpha (1, 3)fucosyltransferase gene family. Multiple homologous sequences that determine expression of the Lewis x, sialyl Lewis x, and difucosyl sialyl Lewis x epitopes. J. Biol. Chem. 267, 24575–24584 (1992)

    PubMed  CAS  Google Scholar 

  35. Lowe, J.B., Kukowska-Latallo, J.F., Nair, R.P., Larsen, R.D., Marks, R.M., Macher, B.A., Kelly, R.J., Ernst, L.K.: Molecular cloning of a human fucosyltransferase gene that determines expression of the Lewis x and VIM-2 epitopes but not ELAM-1-dependent cell adhesion. J. Biol. Chem. 266, 17467–17477 (1991)

    PubMed  CAS  Google Scholar 

  36. Carvalho, A.S., Harduin-Lepers, A., Magalhaes, A., Machado, E., Mendes, N., Costa, L.T., Matthiesen, R., Almeida, R., Costa, J., Reis, C.A.: Differential expression of alpha-2, 3-sialyltransferases and alpha-1, 3/4-fucosyltransferases regulates the levels of sialyl Lewis a and sialyl Lewis x in gastrointestinal carcinoma cells. Int. J. Biochem. Cell Biol. 42, 80–89 (2010)

    Article  PubMed  CAS  Google Scholar 

  37. Mejias-Luque, R., Lopez-Ferrer, A., Garrido, M., Fabra, A., de Bolos, C.: Changes in the invasive and metastatic capacities of HT-29/M3 cells induced by the expression of fucosyltransferase 1. Cancer Sci. 98, 1000–1005 (2007)

    Article  PubMed  CAS  Google Scholar 

  38. Higai, K., Miyazaki, N., Azuma, Y., Matsumoto, K.: Interleukin-1beta induces sialyl Lewis X on hepatocellular carcinoma HuH-7 cells via enhanced expression of ST3Gal IV and FUT VI gene. FEBS Lett. 580, 6069–6075 (2006)

    Article  PubMed  CAS  Google Scholar 

  39. Groux-Degroote, S., Krzewinski-Recchi, M.A., Cazet, A., Vincent, A., Lehoux, S., Lafitte, J.J., Van Seuningen, I., Delannoy, P.: IL-6 and IL-8 increase the expression of glycosyltransferases and sulfotransferases involved in the biosynthesis of sialylated and/or sulfated Lewisx epitopes in the human bronchial mucosa. Biochem. J. 410, 213–223 (2008)

    Article  PubMed  CAS  Google Scholar 

  40. Laporte, B., Gonzalez-Hilarion, S., Maftah, A., Petit, J.M.: The second bovine beta-galactoside-alpha2, 6-sialyltransferase (ST6Gal II): genomic organization and stimulation of its in vitro expression by IL-6 in bovine mammary epithelial cells. Glycobiology 19, 1082–1093 (2009)

    Article  PubMed  CAS  Google Scholar 

  41. Moehler, T.M., Sauer, S., Witzel, M., Andrulis, M., Garcia-Vallejo, J.J., Grobholz, R., Willhauck-Fleckenstein, M., Greiner, A., Goldschmidt, H., Schwartz-Albiez, R.: Involvement of alpha 1-2-fucosyltransferase I (FUT1) and surface-expressed Lewis(y) (CD174) in first endothelial cell-cell contacts during angiogenesis. J. Cell. Physiol. 215, 27–36 (2008)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the AGAUR, Generalitat de Catalunya [2009SGR121], and it is part of M. Padró PhD project at Universitat Pompeu Fabra (Barcelona). Authors thank the scientists providing the antibodies, Dr. Òscar Fornas for flow cytometry analysis, Sergi Mojal for statistical analysis, and Laura Camacho for technical assistance.

Author information

Authors and Affiliations

  1. Programa de Recerca en Càncer, IMIM-Hospital del Mar, 08003, Barcelona, Spain

    Mercè Padró, Raquel Mejías-Luque, Lara Cobler, Marta Garrido, Sònia Puig & Carme de Bolós

  2. Unitat de Bioquimica i Biologia Molecular, Departament de Biologia, Universitat de Girona, 17071, Girona, Spain

    Marta Pérez-Garay & Rosa Peracaula

Authors
  1. Mercè Padró
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raquel Mejías-Luque
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lara Cobler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marta Garrido
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marta Pérez-Garay
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sònia Puig
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rosa Peracaula
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carme de Bolós
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carme de Bolós.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Padró, M., Mejías-Luque, R., Cobler, L. et al. Regulation of glycosyltransferases and Lewis antigens expression by IL-1β and IL-6 in human gastric cancer cells. Glycoconj J 28, 99–110 (2011). https://doi.org/10.1007/s10719-011-9327-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10719-011-9327-4

Keywords

Search

Navigation