title: Mouse model of proximal colon-specific tumorigenesis driven by microsatellite instability-induced Cre-mediated inactivation of Apc and activation of Kras.
abstract: BACKGROUND
  KRAS gene mutations are found in 40-50% of colorectal cancer cases, but their functional contribution is not fully understood. To address this issue, we generated genetically engineered mice with colon tumors expressing an oncogenic Kras(G12D) allele in the context of the Adenomatous polyposis coli (Apc) deficiency to compare them to tumors harboring Apc deficiency alone.
  
  
  METHODS
  CDX2P9.5-G22Cre (referred to as G22Cre) mice showing inducible Cre recombinase transgene expression in the proximal colon controlled under the CDX2 gene promoter were intercrossed with Apc (flox/flox) mice and LSL-Kras (G12D) mice carrying loxP-flanked Apc and Lox-Stop-Lox oncogenic Kras(G12D) alleles, respectively, to generate G22Cre; Apc(flox/flox); Kras(G12D) and G22Cre; Apc(flox/flox); KrasWT mice. Gene expression profiles of the tumors were analyzed using high-density oligonucleotide arrays.
  
  
  RESULTS
  Morphologically, minimal difference in proximal colon tumor was observed between the two mouse models. Consistent with previous findings in vitro, Glut1 transcript and protein expression was up-regulated in the tumors of G22Cre;Apc (flox/flox) ; Kras(G12D) mice. Immunohistochemical staining analysis revealed that GLUT1 protein expression correlated with KRAS mutations in human colorectal cancer. Microarray analysis identified 11 candidate genes upregulated more than fivefold and quantitative PCR analysis confirmed that Aqp8, Ttr, Qpct, and Slc26a3 genes were upregulated 3.7- to 30.2-fold in tumors with mutant Kras.
  
  
  CONCLUSIONS
  These results demonstrated the validity of the G22Cre; Apc(flox/flox) ;Kras (G12D) mice as a new mouse model with oncogenic Kras activation. We believe that this model can facilitate efforts to define novel factors that contribute to the pathogenesis of human colorectal cancer with KRAS mutations.
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kawaguchi
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan. thinoi@hiroshima-u.ac.jp.
authors.forename: Takao
authors.initials: T
authors.lastname: Hinoi
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Adachi
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Miguchi
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niitsu
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Tatsunari
authors.initials: T
authors.lastname: Sasada
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Shimomura
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Egi
authors.affiliation: Department of Endoscopy and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Oka
authors.affiliation: Department of Endoscopy and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology and Metabolism, Applied life sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Department of Molecular Pathology, Applied life sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sentani
authors.affiliation: Department of Molecular Pathology, Applied life sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Naohide
authors.initials: N
authors.lastname: Oue
authors.affiliation: Department of Molecular Pathology, Applied life sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima, 7348551, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D063646:Carcinogenesis; D003106:Colon; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000235:genetics; D006801:Humans; D019426:Integrases / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053842:Microsatellite Instability; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051272:Glucose Transporter Type 1; C495678:Slc2a1 protein, mouse; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Colorectal cancer; Glut1; Kras