Haploinsufficiency of Krüppel-like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis.
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.
Ghaleb
Amr M
AM
Division of Digestive Diseases, Department of Medicine, and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30033, USA.
McConnell
Beth B
BB
Nandan
Mandayam O
MO
Katz
Jonathan P
JP
Kaestner
Klaus H
KH
Yang
Vincent W
VW
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005260:Female; D007124:Immunoenzyme Techniques; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D056741:Cyclin D; D016213:Cyclins; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D051176:beta Catenin