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

Content Provider	PubMed Central
Author	Yang, Kan Popova, Natalia V. Yang, Wancai Lozonschi, Ioanna Tadesse, Selam Kent, Scott Bancroft, Laura Matise, Ilze Cormier, Robert T. Scherer, Stefan J. Edelmann, Winfried Lipkin, Martin Leonard, Augenlicht Anna, Velcich
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 demonstrated 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 2 mouse models, Apc 1638N/+ and Apc Min/+, each of which carries an inactivated Apc allele. The introduction of mutant Muc2 into Apc 1638N/+ and Apc Min/+ mice greatly increased transformation induced by the Apc mutation and significantly shifted tumor development towards the colon, as a function of Muc2 gene dosage. Furthermore, we demonstrated 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 Apc Min/+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.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-08-0598
Ending Page	7322
Page Count	10
Starting Page	7313
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	18
Volume Number	68
Language	English
Publisher Date	2008-09-15
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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