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The secondary bile acid, deoxycholate accelerates intestinal adenoma–adenocarcinoma sequence in Apc min/+ mice through enhancing Wnt signaling

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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.

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References

  1. CDCUS (2009) United States Cancer Statistics: 1999–2005 incidence and mortality web-based report Atlanta [Online]. Cancer Statistics Working Group, Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute. http://apps.nccd.cdc.gov/uscs/[2009]

  2. Castells A, Castellví-Bel S, Balaguer F (2009) Concepts in familial colorectal cancer: where do we stand and what is the future? Gastroenterology 137:404–409

    Article  PubMed  Google Scholar 

  3. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H (2005) Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res 589:47–65

    Article  CAS  PubMed  Google Scholar 

  4. Bajor A, Gillberg PG, Abrahamsson H (2010) Bile acids: short and long term effects in the intestine. Scand J Gastroenterol 45:645–664

    Article  PubMed  Google Scholar 

  5. Pai R, Tarnawski AS, Tran T (2004) Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness. Mol Biol Cell 15:2156–2163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Ignacio Barrasa J, Olmo N, Pérez-Ramos P et al (2011) Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells. Apoptosis 16:1054–1067

    Article  PubMed  Google Scholar 

  7. Payne CM, Crowley-Skillicorn C, Holubec H et al (2009) Deoxycholate, an endogenous cytotoxin/genotoxin, induces the autophagic stress-survival pathway: implications for colon carcinogenesis. J Toxicol 2009:785907

    Article  PubMed Central  PubMed  Google Scholar 

  8. Jean-Louis S, Akare S, Ali MA, Mash EA Jr, Meuillet E et al (2006) Deoxycholic acid induces intracellular signaling through membrane perturbations. J Biol Chem 281:14948–14960

    Article  CAS  PubMed  Google Scholar 

  9. Bernstein C, Holubec H, Bhattacharyya AK et al (2011) Carcinogenicity of deoxycholate, a secondary bile acid. Arch Toxicol 85:863–871

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Payne CM, Holubec H, Bhattacharyya AK, Bernstein C, Bernstein H (2010) Exposure of mouse colon to dietary bile acid supplement induces sessile adenomas. Inflamm Bowel Dis 16:729–730

    Article  PubMed  Google Scholar 

  11. Powell SM, Zilz N, Beazer-Barclay Y et al (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359:235–237

    Article  CAS  PubMed  Google Scholar 

  12. Miyoshi Y, Nagase H, Ando H et al (1992) Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1:229–233

    Article  CAS  PubMed  Google Scholar 

  13. Lee SH, Hu LL, Gonzalez-Navajas J et al (2010) ERK activation drives intestinal tumorigenesis in Apc(min/+) mice. Nat Med 16:665–670

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C et al (1995) Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc Natl Acad Sci U S A 92:4482–4486

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Moser AR, Pitot HC, Dove WF (1990) A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247:322–324

    Article  CAS  PubMed  Google Scholar 

  16. Pishvaian MJ, Byers SW (2007) Biomarkers of WNT signaling. Cancer Biomarkers 3:263–274

    CAS  PubMed  Google Scholar 

  17. Oyama T, Yamada Y, Hata K et al (2008) Further upregulation of beta-catenin/Tcf transcription is involved in the development of macroscopic tumors in the colon of ApcMin/+ mice. Carcinogenesis 29:666–672

    Article  CAS  PubMed  Google Scholar 

  18. Wasan HS, Novelli M, Bee J, Bodmer WF (1997) Dietary fat influences on polyp phenotype in multiple intestinal neoplasia mice. Proc Natl Acad Sci U S A 94:3308–3313

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Rajamanickam S, Velmurugan B, Kaur M, Singh RP, Agarwal R (2010) Chemoprevention of intestinal tumorigenesis in APCmin/+ mice by silibinin. Cancer Res 70:2368–2378

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Mahmoud NN, Dannenberg AJ, Bilinski RT et al (1999) Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis. Carcinogenesis 20:299–303

    Article  CAS  PubMed  Google Scholar 

  21. Shen G, Khor TO, Hu R et al (2007) Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in ApcMin/+ mouse. Cancer Res 67:9937–9944

    Article  CAS  PubMed  Google Scholar 

  22. Smith DL, Keshavan P, Avissar U, Ahmed K, Zucker SD (2010) Sodium taurocholate inhibits intestinal adenoma formation in APCMin/+ mice, potentially through activation of the farnesoid X receptor. Carcinogenesis 31:1100–1109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Velmurugan B, Singh RP, Kaul N, Agarwal R, Agarwal C (2010) Dietary feeding of grape seed extract prevents intestinal tumorigenesis in APCmin/+ mice. Neoplasia 12:95–102

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Bernstein H, Bernstein C, Payne CM, Dvorak K (2009) Bile acids as endogenous etiologic agents in gastrointestinal cancer. World J Gastroenterol 15:3329–3340

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Bayerdörffer E, Mannes GA, Richter WO et al (1993) Increased serum deoxycholic acid levels in men with colorectal adenomas. Gastroenterology 104:145–151

    PubMed  Google Scholar 

  26. Ochsenkühn T, Bayerdörffer E, Meining A et al (1999) Colonic mucosal proliferation is related to serum deoxycholic acid levels. Cancer 85:1664–1669

    Article  PubMed  Google Scholar 

  27. Fracchia M, Galatola G, Sarotto I et al (2005) Serum bile acids, programmed cell death and cell proliferation in the mucosa of patients with colorectal adenomas. Dig Liver Dis 37:509–514

    Article  CAS  PubMed  Google Scholar 

  28. Sauer P, Stiehl A, Fitscher BA et al (2000) Downregulation of ileal bile acid absorption in bile-duct-ligated rats. J Hepatol 33:2–8

    Article  CAS  PubMed  Google Scholar 

  29. Li H, Chen F, Shang Q et al (2005) FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade. Am J Physiol Gastrointest Liver Physiol 288:G60–G66

    Article  CAS  PubMed  Google Scholar 

  30. Maga G, Hubscher U (2003) Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci 116:3051–3060

    Article  CAS  PubMed  Google Scholar 

  31. Sansom OJ, Reed KR, Hayes AJ et al (2004) Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18:1385–1390

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Knutsen HK, Olstørn HB, Paulsen JE et al (2005) Increased levels of PPARbeta/delta and cyclin D1 in flat dysplastic ACF and adenomas in Apc(Min/+) mice. Anticancer Res 25:3781–3789

    CAS  PubMed  Google Scholar 

  33. Fu M, Wang C, Li Z, Sakamaki T, Pestell RG (2004) Minireview: cyclin D1: normal and abnormal functions. Endocrinology 145:5439–5447

    Article  CAS  PubMed  Google Scholar 

  34. Khor TO, Gul YA, Ithnin H, Seow HF (2006) A comparative study of the expression of Wnt-1, WISP-1, survivin and cyclin-D1 in colorectal carcinoma. Int J Colorectal Dis 21:291–300

    Article  PubMed  Google Scholar 

  35. He B, Reguart N, You L et al (2005) Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations. Oncogene 24:3054–3058

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study is supported by the Grants (81300272 to H.L.C. and 81070283 to B.M.W.) from the National Natural Science Foundation of China, a Grant (20121202110018 to B.M.W.) from Research Fund for the Doctoral Program of Higher Education of China, and a Grant (13JCQNJC10600 to H.L.C.) from Tianjin Research Program of Application Foundation and Advanced Technology of China.

Conflict of interest

The authors have no conflict of interest.

Ethical standards

This study was conducted with the approval of the Institutional Animal Care and Use Committee at Tianjin Medical University, and Ethics Committee of Tianjin General Hospital, Tianjin Medical University, Tianjin, P. R. China.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, 154 Anshan Road in Heping District, Tianjin, 300052, China

    Hailong Cao, Shenhui Luo, Mengque Xu, Shuli Song, Shan Wang, Xinyue Kong, Nana He, Xiaocang Cao, Fang Yan & Bangmao Wang

  2. Department of Gastroenterology, People’s Hospital of Xiangxi Autonomous Prefecture, Ji shou City, Hunan Province, China

    Shenhui Luo

  3. Department of Pathology, General Hospital, Tianjin Medical University, Tianjin, 300052, China

    Yujie Zhang

  4. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Fang Yan

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  1. Hailong Cao
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  2. Shenhui Luo
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  3. Mengque Xu
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  9. Xiaocang Cao
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  10. Fang Yan
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  11. Bangmao Wang
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Correspondence to Bangmao Wang.

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Hailong Cao and Shenhui Luo have contributed equally to this work.

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Cao, H., Luo, S., Xu, M. et al. The secondary bile acid, deoxycholate accelerates intestinal adenoma–adenocarcinoma sequence in Apc min/+ mice through enhancing Wnt signaling. Familial Cancer 13, 563–571 (2014). https://doi.org/10.1007/s10689-014-9742-3

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