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Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors

Oncogene volume 29, pages 1753–1762 (2010)Cite this article

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Abstract

Infection of gastric mucosa by Helicobacter pylori induces an inflammatory response with increased levels of proinflammatory cytokines. Among them, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 induce the activation of signaling pathways that regulate genes expression, such as MUC2 and MUC4 intestinal mucins ectopically detected in gastric tumors. This study evaluated if the predominant inflammatory cell type correlates with MUC2 and MUC4 expression in human intestinal gastric tumors (n=78). In addition, we analyzed the regulatory effects of the associated inflammatory signaling pathways on their expression in gastric cancer cell lines, and in a mouse model with hyperactivated STAT3 signaling pathway. Tumors with predominant lymphoplasmocytic infiltrate (chronic inflammation), presented higher levels of MUC2 and were more differentiated than tumors with predominant polymorphonuclear infiltrate (acute inflammation). These differences can be attributed to specific cytokines, because TNF-α and IL-1β induced MUC2 but no MUC4 expression in gastric cancer cell lines. The two groups of tumors expressed similar levels of MUC4 that correlated with the expression of STAT3 transcription factor, implicated in the activation of genes through the IL-6 pathway. In gastric tissues from gp130+/+, gp130Y757F/Y757F and gp130Y757F/Y757F Stat3−/+ mice, Muc2 was not detected, whereas Muc4 was found in the gastric tumors developed in the gp130Y757F/Y757F mice, with hyperactivated STAT3. These data indicate that the signaling pathways associated with the inflammatory response can modulate the expression of MUC2 and MUC4 intestinal mucin genes, in human and mouse gastric tumors.

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Acknowledgements

We thank the scientists providing the antibodies, Sergi Mojal for statistical analysis, and M Pera, A Dalmases, P Navarro and J Gunnarsson for helpful contributions. This work was supported by Marató de TV3 (050930), Instituto de Investigación Carlos III (PI061421), the Swedish Cancer Foundation and Research Counsil (Cancerfonden and Vetenskapsrådet) and the Jeansson foundation, Sylvia and Charles Viertel Charitable Foundation Senior Medical Research Fellowship, Monash University Fellowship, Cancer Council of Victoria Grant-in-aid, and the Association for International Cancer Research Grant awarded to BJJ.

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Authors and Affiliations

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

    R Mejías-Luque, M Garrido, M Iglesias & C de Bolós

  2. Mucosal Immunobiology and Vaccine Center, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

    S K Lindén

  3. Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, Victoria, Australia

    H Tye, M Najdovska & B J Jenkins

  4. Ludwig Institute for Cancer Research, Victoria, Australia

    M Ernst

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  1. R Mejías-Luque
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  2. S K Lindén
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  3. M Garrido
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  9. C de Bolós
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Correspondence to C de Bolós.

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Mejías-Luque, R., Lindén, S., Garrido, M. et al. Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors. Oncogene 29, 1753–1762 (2010). https://doi.org/10.1038/onc.2009.467

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