Interaction of Muc2 and Apc on Wnt signaling and in intestinal tumorigenesis: potential role of chronic inflammation.
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, 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 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 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.
Yang
Kan
K
Strang Cancer Center at New York Blood Bank, New York, USA.
Popova
Natalia V
NV
Yang
Wan Cai
WC
Lozonschi
Ioanna
I
Tadesse
Selam
S
Kent
Scott
S
Bancroft
Laura
L
Matise
Ilze
I
Cormier
Robert T
RT
Scherer
Stefan J
SJ
Edelmann
Winfried
W
Lipkin
Martin
M
Augenlicht
Leonard
L
Velcich
Anna
A
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004760:Enterocolitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D017491:Genes, APC; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D055262:Mucin-2; D009077:Mucins / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D051153:Wnt Proteins; D051176:beta Catenin
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