title: Disruption of Klf4 in villin-positive gastric progenitor cells promotes formation and progression of tumors of the antrum in mice.
abstract: OBJECTIVE
  Krüppel-like factor 4 (Klf4) is a putative gastric tumor suppressor gene. Rare, villin-positive progenitor cells in the gastric antrum have multilineage potential. We investigated the function of Klf4 in these cells and in gastric carcinogenesis.
  
  
  METHODS
  We created mice with disruption of Klf4 in villin-positive antral mucosa cells (Villin-Cre(+);Klf4(fl/fl) mice). Villin-Cre(+);Klf4(fl/fl) and control mice were given drinking water with or without 240 ppm N-methyl-N-nitrosourea at 5 weeks of age and thereafter on alternating weeks for a total of 10 weeks. Gastric mucosa samples were collected at 35, 50, or 80 weeks of age from mice that were and were not given N-methyl-N-nitrosourea, and analyzed by histopathologic and molecular analyses. Findings were compared with those from human gastric tumor specimens.
  
  
  RESULTS
  Preneoplasia formed progressively in the antrum in 35- to 80-week-old Villin-Cre(+);Klf4(fl/fl) mice. Gastric tumors developed in 29% of 80-week-old Villin-Cre(+);Klf4(fl/fl) mice, which were located exclusively in the lesser curvature of the antrum. N-methyl-N-nitrosourea accelerated tumor formation, and tumors developed significantly more frequently in Villin-Cre(+);Klf4(fl/fl) mice than in control mice, at 35 and 50 weeks of age. Mouse and human gastric tumors had reduced expression of Krüppel-like factor 4 and increased expression of FoxM1 compared with healthy gastric tissue. Expression of Krüppel-like factor 4 suppressed transcription of FoxM1.
  
  
  CONCLUSIONS
  Inactivation of Klf4 in villin-positive gastric progenitor cells induces transformation of the gastric mucosa and tumorigenesis in the antrum in mice. Villin-Cre(+);Klf4(fl/fl) have greater susceptibility to chemical-induced gastric carcinogenesis and increased rates of gastric tumor progression than control mice.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Jia
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Kong
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Kun
authors.initials: K
authors.lastname: Guo
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Tan
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Le
authors.forename: Daoyan
authors.initials: D
authors.lastname: Wei
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008770:Methylnitrosourea; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011706:Pyloric Antrum / Q000378:metabolism* / Q000473:pathology; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008840:Microfilament Proteins; C026615:villin; D008770:Methylnitrosourea; C045073:Cre recombinase; D019426:Integrases