title: Gene expression analysis of a Helicobacter pylori-infected and high-salt diet-treated mouse gastric tumor model: identification of CD177 as a novel prognostic factor in patients with gastric cancer.
abstract: BACKGROUND
  Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model.
  
  
  METHODS
  To find candidate genes involved in stomach carcinogenesis, we firstly constructed a carcinogen-induced mouse gastric tumor model combined with H. pylori infection and high-salt diet. C57BL/6J mice were given N-methyl-N-nitrosourea in their drinking water and sacrificed after 40 weeks. Animals of a combination group were inoculated with H. pylori and fed a high-salt diet. Gene expression profiles in glandular stomach of the mice were investigated by oligonucleotide microarray. Second, we examined an availability of the candidate gene as prognostic factor for human patients. Immunohistochemical analysis of CD177, one of the up-regulated genes, was performed in human advanced gastric cancer specimens to evaluate the association with prognosis.
  
  
  RESULTS
  The multiplicity of gastric tumor in carcinogen-treated mice was significantly increased by combination of H. pylori infection and high-salt diet. In the microarray analysis, 35 and 31 more than two-fold up-regulated and down-regulated genes, respectively, were detected in the H. pylori-infection and high-salt diet combined group compared with the other groups. Quantitative RT-PCR confirmed significant over-expression of two candidate genes including Cd177 and Reg3g. On immunohistochemical analysis of CD177 in human advanced gastric cancer specimens, over-expression was evident in 33 (60.0%) of 55 cases, significantly correlating with a favorable prognosis (P = 0.0294). Multivariate analysis including clinicopathological factors as covariates revealed high expression of CD177 to be an independent prognostic factor for overall survival.
  
  
  CONCLUSIONS
  These results suggest that our mouse model combined with H. pylori infection and high-salt diet is useful for gene expression profiling in gastric carcinogenesis, providing evidence that CD177 is a novel prognostic factor for stomach cancer. This is the first report showing a prognostic correlation between CD177 expression and solid tumor behavior.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Toyoda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Masami
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hisayo
authors.initials: H
authors.lastname: Ban
authors.forename: Noriko
authors.initials: N
authors.lastname: Saito
authors.forename: Shinji
authors.initials: S
authors.lastname: Takasu
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.forename: Ayumi
authors.initials: A
authors.lastname: Saito
authors.forename: Seiji
authors.initials: S
authors.lastname: Ito
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yamamura
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masae
authors.initials: M
authors.lastname: Tatematsu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins / Q000032:analysis / Q000235:genetics; D005753:Gastric Mucosa / Q000737:chemistry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000150:complications*; D016480:Helicobacter pylori; D006801:Humans; D007150:Immunohistochemistry; D007519:Isoantigens / Q000032:analysis / Q000235:genetics*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D000073718:Pancreatitis-Associated Proteins; D011379:Prognosis; D011506:Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics*; D012982:Sodium, Dietary / Q000009:adverse effects*; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics*
chemical_list: C407242:CD177 protein, human; D058851:GPI-Linked Proteins; D007519:Isoantigens; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C494437:REG3G protein, human; D011956:Receptors, Cell Surface; D012982:Sodium, Dietary
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13687-92
references.pmid: 11717430
references.citation: Cancer Sci. 2005 May;96(5):265-73
references.pmid: 15904467
references.citation: Biochem Biophys Res Commun. 2005 Aug 26;334(2):606-12
references.pmid: 16009342
references.citation: Gastroenterology. 2012 Apr;142(4):824-833.e7
references.pmid: 22248660
references.citation: Toxicol Pathol. 2007 Aug;35(5):636-48
references.pmid: 17654405
references.citation: Biochem Biophys Res Commun. 2001 Jun 8;284(2):443-9
references.pmid: 11394899
references.citation: Cancer Sci. 2009 Oct;100(10):1779-85
references.pmid: 19622104
references.citation: J Gastroenterol. 1999;34 Suppl 11:61-6
references.pmid: 10616768
references.citation: N Engl J Med. 2001 Sep 13;345(11):784-9
references.pmid: 11556297
references.citation: Eur J Immunol. 2001 May;31(5):1301-9
references.pmid: 11465086
references.citation: Int J Cancer. 2009 Oct 15;125(8):1786-95
references.pmid: 19610061
references.citation: J Biol Chem. 2001 May 25;276(21):18327-36
references.pmid: 11278439
references.citation: Cancer Causes Control. 1996 Jan;7(1):41-55
references.pmid: 8850434
references.citation: Int J Epidemiol. 1996 Jun;25(3):494-504
references.pmid: 8671549
references.citation: J Transl Med. 2004 Mar 29;2(1):8
references.pmid: 15050027
references.citation: Cancer Res. 2002 Dec 1;62(23):7012-7
references.pmid: 12460921
references.citation: Cancer Sci. 2005 Jan;96(1):1-6
references.pmid: 15649247
references.citation: Cancer Res. 2003 May 15;63(10):2569-77
references.pmid: 12750281
references.citation: Int J Cancer. 2001 Jun 15;92(6):832-8
references.pmid: 11351303
references.citation: Cytogenet Cell Genet. 1998;83(1-2):104-8
references.pmid: 9925946
references.citation: Carcinogenesis. 2003 May;24(5):861-7
references.pmid: 12771029
references.citation: Jpn J Cancer Res. 2002 Oct;93(10):1083-9
references.pmid: 12417037
references.citation: Cancer Sci. 2007 Mar;98(3):284-93
references.pmid: 17270017
references.citation: J Clin Invest. 2008 Jun;118(6):2325-36
references.pmid: 18483624
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: J Gastroenterol Hepatol. 2008 Mar;23(3):351-65
references.pmid: 18318820
references.citation: Int J Immunopathol Pharmacol. 2008 Jul-Sep;21(3):515-26
references.pmid: 18831919
references.citation: Cancer Sci. 2008 Dec;99(12):2356-64
references.pmid: 19018769
references.citation: Int J Cancer. 2006 Oct 1;119(7):1558-66
references.pmid: 16646055
references.citation: Ann Surg Oncol. 2012 Apr;19(4):1240-9
references.pmid: 22048633
references.citation: Cancer Prev Res (Phila). 2009 Aug;2(8):751-8
references.pmid: 19622613
references.citation: Mod Pathol. 2007 Sep;20(9):974-89
references.pmid: 17643099
references.citation: Histol Histopathol. 2008 May;23(5):593-9
references.pmid: 18283644
references.citation: Cancer Res. 2002 Jan 1;62(1):233-40
references.pmid: 11782383
references.citation: Infect Immun. 2004 Aug;72(8):4668-79
references.pmid: 15271928
references.citation: Mod Pathol. 2009 Jul;22(7):906-13
references.pmid: 19329938
references.citation: J Histochem Cytochem. 2007 Mar;55(3):263-74
references.pmid: 17101721
references.citation: Infect Immun. 2004 Sep;72(9):5216-26
references.pmid: 15322016
references.citation: Gastric Cancer. 2003;6(1):1-7
references.pmid: 12673420
references.citation: Gastric Cancer. 1998 Dec;1(1):10-24
references.pmid: 11957040