Interaction of Muc2 and Apc on Wnt signaling and in intestinal tumorigenesis: Potential role of chronic inflammation

Kan Yang, Natalia V. Popova, Cai Yang Wan, Ioanna Lozonschi, Selam Tadesse, Scott Kent, Laura Bancroft, Ilze Matise, Robert T. Cormier, Stefan J. Scherer, Winfried Edelmann, Martin Lipkin, Leonard Augenlicht, Anna Velcich

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73 Scopus citations

Abstract

Somatic mutations of the adenomatous polyposis coli (APC) gene are initiating events in the majority of sporadic colon cancers. A common characteristic of such tumors is reduction in the number of goblet cells that produce the mucin MUC2, the principal component of intestinal mucus. Consistent with these observations, we showed that Muc2 deficiency results in the spontaneous development of tumors along the entire gastrointestinal tract, independently of deregulated Wnt signaling. To dissect the complex interaction between Muc2 and Apc in intestinal tumorigenesis and to elucidate the mechanisms of tumor formation in Muc2-/- mice, we crossed the Muc2 -/- mouse with two mouse models, Apc1638N/+ and Apc Min/+, each of which carries an inactivated Apc allele. The introduction of mutant Muc2 into Apc1638N/+ and ApcMin/+ mice greatly increased transformation induced by the Apc mutation and significantly shifted tumor development toward the colon as a function of Muc2 gene dosage. Furthermore, we showed that in compound double mutant mice, deregulation of Wnt signaling was the dominant mechanism of tumor formation. The increased tumor burden in the distal colon of Muc2/Apc double mutant mice was similar to the phenotype observed in ApcMin/+ mice that are challenged to mount an inflammatory response, and consistent with this, gene expression profiles of epithelial cells from flat mucosa of Muc2-deficient mice suggested that Muc2 deficiency was associated with low levels of subclinical chronic inflammation. We hypothesize that Muc2-/- tumors develop through an inflammation-related pathway that is distinct from and can complement mechanisms of tumorigenesis in Apc+/- mice.

Original languageEnglish (US)
Pages (from-to)7313-7322
Number of pages10
JournalCancer Research
Volume68
Issue number18
DOIs
StatePublished - Sep 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Yang, K., Popova, N. V., Wan, C. Y., Lozonschi, I., Tadesse, S., Kent, S., Bancroft, L., Matise, I., Cormier, R. T., Scherer, S. J., Edelmann, W., Lipkin, M., Augenlicht, L., & Velcich, A. (2008). Interaction of Muc2 and Apc on Wnt signaling and in intestinal tumorigenesis: Potential role of chronic inflammation. Cancer Research, 68(18), 7313-7322. https://doi.org/10.1158/0008-5472.CAN-08-0598