title: Interaction of Muc2 and Apc on Wnt signaling and in intestinal tumorigenesis: potential role of chronic inflammation.
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, 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.
authors.affiliation: Strang Cancer Center at New York Blood Bank, New York, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Yang
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Popova
authors.forename: Wan Cai
authors.initials: WC
authors.lastname: Yang
authors.forename: Ioanna
authors.initials: I
authors.lastname: Lozonschi
authors.forename: Selam
authors.initials: S
authors.lastname: Tadesse
authors.forename: Scott
authors.initials: S
authors.lastname: Kent
authors.forename: Laura
authors.initials: L
authors.lastname: Bancroft
authors.forename: Ilze
authors.initials: I
authors.lastname: Matise
authors.forename: Robert T
authors.initials: RT
authors.lastname: Cormier
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Martin
authors.initials: M
authors.lastname: Lipkin
authors.forename: Leonard
authors.initials: L
authors.lastname: Augenlicht
authors.forename: Anna
authors.initials: A
authors.lastname: Velcich
mesh_terms: 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
chemical_list: C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D051153:Wnt Proteins; D051176:beta Catenin
references.citation: Cancer Res. 2006 Sep 1;66(17):8430-8
references.pmid: 16951153
references.citation: J Clin Invest. 2006 May;116(5):1310-6
references.pmid: 16670770
references.citation: Curr Opin Gastroenterol. 2007 Mar;23(2):115-20
references.pmid: 17268238
references.citation: J Exp Med. 2006 Mar 20;203(3):541-52
references.pmid: 16505137
references.citation: J Exp Med. 2006 Oct 30;203(11):2473-83
references.pmid: 17030949
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4610-5
references.pmid: 12668767
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13927-31
references.pmid: 9391129
references.citation: Cancer Res. 2004 Sep 1;64(17):6050-7
references.pmid: 15342386
references.citation: J Immunol. 2007 Oct 15;179(8):5474-82
references.pmid: 17911634
references.citation: Cell. 2004 Sep 17;118(6):671-4
references.pmid: 15369667
references.citation: Cancer Sci. 2005 Feb;96(2):69-76
references.pmid: 15723650
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15370-5
references.pmid: 15492215
references.citation: J Clin Invest. 2006 May;116(5):1218-22
references.pmid: 16670765
references.citation: Science. 1992 May 1;256(5057):668-70
references.pmid: 1350108
references.citation: Nat Cell Biol. 2007 Dec;9(12):1419-27
references.pmid: 18037881
references.citation: Oncogene. 2004 May 6;23(21):3813-21
references.pmid: 15021908
references.citation: Science. 2002 Mar 1;295(5560):1726-9
references.pmid: 11872843
references.citation: Cancer Res. 2001 Nov 1;61(21):7934-42
references.pmid: 11691815
references.citation: Cancer Res. 2003 May 15;63(10):2388-92
references.pmid: 12750256
references.citation: Carcinogenesis. 2005 Sep;26(9):1513-9
references.pmid: 15860506
references.citation: Cell. 1996 Nov 29;87(5):803-9
references.pmid: 8945508
references.citation: Int J Cancer. 2006 Jan 1;118(1):25-34
references.pmid: 16049979
references.citation: Cell. 1991 Aug 9;66(3):589-600
references.pmid: 1651174
references.citation: J Immunol. 2004 Sep 15;173(6):3668-75
references.pmid: 15356112
references.citation: J Cell Biol. 2004 Jul 5;166(1):37-47
references.pmid: 15240568
references.citation: J Med Genet. 1999 Nov;36(11):859-60
references.pmid: 10636731
references.citation: Gastroenterology. 2000 Feb;118(2):337-45
references.pmid: 10648462
references.citation: Biochim Biophys Acta. 2006 Apr;1765(2):189-222
references.pmid: 16487661
references.citation: Nat Rev Cancer. 2004 Jan;4(1):45-60
references.pmid: 14681689
references.citation: Cancer Res. 2007 Oct 15;67(20):9937-44
references.pmid: 17942926
references.citation: Science. 1991 Aug 9;253(5020):665-9
references.pmid: 1651563
references.citation: Curr Opin Genet Dev. 1999 Feb;9(1):15-21
references.pmid: 10072352
references.citation: Biochim Biophys Acta. 2005 Nov 25;1756(2):83-96
references.pmid: 16219426
references.citation: Br J Cancer. 1999 Mar;79(9-10):1399-405
references.pmid: 10188882
references.citation: J Clin Invest. 1991 Sep;88(3):1005-13
references.pmid: 1885763
references.citation: Mucosal Immunol. 2008 May;1(3):183-97
references.pmid: 19079178
references.citation: J Clin Invest. 2006 Nov;116(11):2914-23
references.pmid: 17024245
references.citation: Gastroenterology. 2006 Jul;131(1):117-29
references.pmid: 16831596
references.citation: Drug Metab Dispos. 2004 Apr;32(4):437-41
references.pmid: 15039297
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8969-73
references.pmid: 8090754
references.citation: Carcinogenesis. 1997 Feb;18(2):321-7
references.pmid: 9054624
references.citation: Gut. 2001 Mar;48(3):326-32
references.pmid: 11171821
references.citation: Annu Rev Pharmacol Toxicol. 2006;46:123-49
references.pmid: 16402901
references.citation: Semin Immunol. 2007 Apr;19(2):70-83
references.pmid: 17485224
references.citation: Nature. 2004 Dec 16;432(7019):917-21
references.pmid: 15531878
references.citation: Trends Biochem Sci. 2005 Aug;30(8):453-61
references.pmid: 15996871
references.citation: Science. 2006 Aug 25;313(5790):1126-30
references.pmid: 16931762
references.citation: Cancer Res. 2007 Oct 15;67(20):9721-30
references.pmid: 17942902
references.citation: Science. 1991 Aug 9;253(5020):661-5
references.pmid: 1651562
references.citation: Annu Rev Cell Dev Biol. 2004;20:695-723
references.pmid: 15473857