title: KLF4-mediated negative regulation of IFITM3 expression plays a critical role in colon cancer pathogenesis.
abstract: OBJECTIVE
  IFITM3, an IFN-inducible gene, is overexpressed in human colorectal cancer. In this study, we sought to determine the clinical significance and underlying mechanisms of its dysregulated expression in human colon tumor specimens and murine models of this disease.
  
  
  METHODS
  IFITM3 expression in a tissue microarray of tumor and matched normal colon tissue specimens and lymph node metastasis specimens obtained from 203 patients with colon cancer was measured immunohistochemically.
  
  
  RESULTS
  IFITM3 was expressed at higher levels in colon tumors and, particularly, nodal metastases than in normal colon tissue. A Cox proportional hazards model showed that IFITM3 expression was an independent prognostic factor for disease-free survival in patients with colon cancer. Knockdown of IFITM3 expression by a specific siRNA significantly suppressed the proliferation, colony formation, migration, and invasion of colon cancer cells in vitro and tumor growth and metastasis in a xenograft model. Restored expression of KLF4, a putative tumor suppressor, downregulated IFITM3 expression in colon cancer cells in vitro. Two KLF4-binding sites in the IFITM3 promoter bound specifically to KLF4 protein in a chromatin immunoprecipitation assay and promoter mutagenesis analyses. Specific deletion of KLF4 led to IFITM3 overexpression in colon mucosa in Villin-Cre(+);Klf4(fl/fl) mice. An inverse correlation between loss of KLF4 expression and IFITM3 overexpression was evident in human colon tumors.
  
  
  CONCLUSIONS
  These clinical and mechanistic findings indicate that IFITM3 is a direct transcriptional target of KLF4 and that dysregulated KLF4 expression leads to aberrant IFITM3 expression, thus contributing to colon cancer progression and metastasis.
authors.affiliation: Departments of General Surgery and Pathology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, PR China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Peng
authors.forename: Huamei
authors.initials: H
authors.lastname: Tang
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Kong
authors.forename: Dongwang
authors.initials: D
authors.lastname: Yan
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Le
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: C080082:IFITM3 protein, human; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C462181:fragilis protein, mouse