title: The secondary bile acid, deoxycholate accelerates intestinal adenoma-adenocarcinoma sequence in Apc (min/+) mice through enhancing Wnt signaling.
abstract: Colorectal cancer is one of the leading causes of cancer deaths. It correlates to a high fat diet, which causes an increase of the secondary bile acids including deoxycholate (DOC) in the intestine. We aimed to determine the effects of DOC on intestinal carcinogenesis in Apc (min/+) mice, a model of spontaneous intestinal adenomas. Four-week old Apc (min/+) mice were treated with 0.2 % DOC in drinking water for 12 weeks. The number and size of tumors were measured, and tissue sections were prepared for the evaluation of intestinal carcinogenesis, cell proliferation, and apoptosis. The activation of Wnt signaling was detected in the intestinal tumor cells of the Apc (min/+) mice, and also in the human colon samples. DOC increased the number of intestine tumors by 165.1 % compared with that in untreated Apc (min/+) mice mainly in the middle and distal segments of the small intestine and colon. The numbers of all sizes of tumors in the small intestine were increased. Intestinal carcinogenesis was confirmed in 75 % mice in DOC treated-Apc (min/+) mice compared with 0 % in untreated mice. This was accompanied by promoting tumor cell proliferation and decreasing apoptosis, and increasing the percentage of β-catenin positive cells and its nuclear expression in intestinal tumor cells of Apc (min/+) mice, and also up-regulating the expression of cyclin D1. In addition, the activation of Wnt signaling also played in modulating human colon carcinogenesis. Our studies suggest that DOC enhances the multiplicity of intestinal tumor, and accelerates intestinal adenoma-adenocarcinoma sequence in Apc (min/+) mice mediated by stimulating tumor cell proliferation and decreasing apoptosis through enhancing Wnt signaling.
authors.affiliation: Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, 154 Anshan Road in Heping District, Tianjin, 300052, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Cao
authors.forename: Shenhui
authors.initials: S
authors.lastname: Luo
authors.forename: Mengque
authors.initials: M
authors.lastname: Xu
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shuli
authors.initials: S
authors.lastname: Song
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.forename: Xinyue
authors.initials: X
authors.lastname: Kong
authors.forename: Nana
authors.initials: N
authors.lastname: He
authors.forename: Xiaocang
authors.initials: X
authors.lastname: Cao
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
authors.forename: Bangmao
authors.initials: B
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000236:Adenoma / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D003840:Deoxycholic Acid / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*
chemical_list: D003840:Deoxycholic Acid
references.citation: J Hepatol. 2000 Jul;33(1):2-8
references.pmid: 10905579
references.citation: J Biol Chem. 2006 May 26;281(21):14948-60
references.pmid: 16547009
references.citation: Dig Liver Dis. 2005 Jul;37(7):509-14
references.pmid: 15975538
references.citation: Mutat Res. 2005 Jan;589(1):47-65
references.pmid: 15652226
references.citation: Scand J Gastroenterol. 2010 Jun;45(6):645-64
references.pmid: 20334475
references.citation: Carcinogenesis. 2008 Mar;29(3):666-72
references.pmid: 18204079
references.citation: World J Gastroenterol. 2009 Jul 21;15(27):3329-40
references.pmid: 19610133
references.citation: Cancer. 1999 Apr 15;85(8):1664-9
references.pmid: 10223558
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4482-6
references.pmid: 7753829
references.citation: Genes Dev. 2004 Jun 15;18(12):1385-90
references.pmid: 15198980
references.citation: Nature. 1992 Sep 17;359(6392):235-7
references.pmid: 1528264
references.citation: Int J Colorectal Dis. 2006 May;21(4):291-300
references.pmid: 16041507
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Jan;288(1):G60-6
references.pmid: 15591588
references.citation: Carcinogenesis. 1999 Feb;20(2):299-303
references.pmid: 10069468
references.citation: Mol Biol Cell. 2004 May;15(5):2156-63
references.pmid: 15004225
references.citation: J Toxicol. 2009;2009:785907
references.pmid: 20130808
references.citation: Gastroenterology. 1993 Jan;104(1):145-51
references.pmid: 8419237
references.citation: Cancer Res. 2007 Oct 15;67(20):9937-44
references.pmid: 17942926
references.citation: Anticancer Res. 2005 Nov-Dec;25(6B):3781-9
references.pmid: 16309164
references.citation: Arch Toxicol. 2011 Aug;85(8):863-71
references.pmid: 21267546
references.citation: Carcinogenesis. 2010 Jun;31(6):1100-9
references.pmid: 20194350
references.citation: Oncogene. 2005 Apr 21;24(18):3054-8
references.pmid: 15735684
references.citation: Science. 1990 Jan 19;247(4940):322-4
references.pmid: 2296722
references.citation: Apoptosis. 2011 Oct;16(10):1054-67
references.pmid: 21789651
references.citation: Nat Med. 2010 Jun;16(6):665-70
references.pmid: 20473309
references.citation: Endocrinology. 2004 Dec;145(12):5439-47
references.pmid: 15331580
references.citation: J Cell Sci. 2003 Aug 1;116(Pt 15):3051-60
references.pmid: 12829735
references.citation: Hum Mol Genet. 1992 Jul;1(4):229-33
references.pmid: 1338904
references.citation: Inflamm Bowel Dis. 2010 May;16(5):729-30
references.pmid: 20135625
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3308-13
references.pmid: 9096389
references.citation: Neoplasia. 2010 Jan;12(1):95-102
references.pmid: 20072658
references.citation: Cancer Biomark. 2007;3(4-5):263-74
references.pmid: 17917155
references.citation: Gastroenterology. 2009 Aug;137(2):404-9
references.pmid: 19540838
references.citation: Cancer Res. 2010 Mar 15;70(6):2368-78
references.pmid: 20215518