PMID:17671182

Citation	Ghaleb, AM, McConnell, BB, Nandan, MO, Katz, JP, Kaestner, KH and Yang, VW (2007) Haploinsufficiency of Krüppel-like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis. Cancer Res. 67:7147-54
Abstract	The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently down-regulated in colorectal cancer. Previous studies showed that the expression of KLF4 was activated by the colorectal cancer tumor suppressor adenomatous polyposis coli (APC) and that KLF4 repressed the Wnt/beta-catenin pathway. Here, we examined whether KLF4 plays a role in modulating intestinal tumorigenesis by comparing the tumor burdens in mice heterozygous for the Apc(Min) allele (Apc(Min/+)) and those heterozygous for both the Apc(Min) and Klf4 alleles (Klf4(+/-)/Apc(Min/+)). Between 10 and 20 weeks of age, Klf4(+/-)/Apc(Min/+) mice developed, on average, 59% more intestinal adenomas than Apc(Min/+) mice (P < 0.0001). Immunohistochemical staining showed that Klf4 protein levels were lower in the normal-appearing intestinal tissues of Klf4(+/-)/Apc(Min/+) mice compared with wild-type, Klf4(+/-), or Apc(Min/+) mice. In contrast, the levels of beta-catenin and cyclin D1 were higher in the normal-appearing intestinal tissues of Klf4(+/-)/Apc(Min/+) mice compared with the other three genotypes. Klf4 levels were further decreased in adenomas from both Apc(Min/+) and Klf4(+/-)/Apc(Min/+) mice compared with their corresponding normal-appearing tissues. Reverse transcription-PCR showed an inverse correlation between adenoma size and Klf4 mRNA levels in both Klf4(+/-)/Apc(Min/+) and Apc(Min/+) mice. There was also a progressive loss of heterozygosity of the wild-type Apc allele in adenomas with increasing size from Klf4(+/-)/Apc(Min/+) and Apc(Min/+) mice. Results from this study show that KLF4 plays an important role in promoting the development of intestinal adenomas in the presence of Apc(Min) mutation.
Links	PubMed PMC2373271 Online version:10.1158/0008-5472.CAN-07-1302
Keywords	Adenoma/genetics; Adenoma/metabolism; Adenoma/pathology; Adenomatous Polyposis Coli/genetics; Adenomatous Polyposis Coli/metabolism; Adenomatous Polyposis Coli/pathology; Animals; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; Cell Transformation, Neoplastic/pathology; Cyclin D; Cyclins/genetics; Cyclins/metabolism; Female; Immunoenzyme Techniques; Intestinal Neoplasms/genetics; Intestinal Neoplasms/metabolism; Intestinal Neoplasms/pathology; Intestinal Polyps/genetics; Intestinal Polyps/metabolism; Intestinal Polyps/pathology; Kruppel-Like Transcription Factors/genetics; Kruppel-Like Transcription Factors/metabolism; Loss of Heterozygosity; Male; Mice; Mice, Inbred C57BL; RNA, Messenger/metabolism; beta Catenin/metabolism
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