KLF-4 may play role in metaplastic changes in Barrett’s oesophagus
MedWire News: Krüppel-like factor (KLF)4 may be involved in metaplastic changes in Barrett's epithelium development, suggest study findings showing that expression of KLF4 in response to bile acids in oesophageal keratinocytes induces metaplastic changes and production of mucin (MUC)2.
"The causal link between bile acid reflux and alternations of some transcription factors has been studied; however, the precise mechanism of promotion of Barrett's epithelium formation by bile acid reflux remains to be characterized," say Hideaki Kazumori (Shimane University, Japan) and co-authors.
KLF4 is an important transcription factor in the development of intestinal mucosa, and has similar functions as Cdx2, which has been previously shown to stimulate production of intestinal-type mucin, say the researchers.
The team investigated expression of KLF4 in rat and human Barrett's epithelium specimens. The response of this expression to bile acids was studied using a KLF4 promoter luciferase assay.
Both human and rat Barrett's epithelium showed strong expression of KLF4. KLF4 mRNA was expressed throughout the gastrointestinal tract of adult rats, with high levels observed in the jejunum, ileum, and proximal and distal colon, with lower level of expression seen in the esophagus. Similarly, KLF4 mRNA expression levels were significantly higher in Barrett's esophagus human tissue samples compared with normal squamous epithelium.
When esophageal epithelial cells were exposed to a bile acids mixture, KLF4 transcriptional promoter activity was increased approximately two fold in a dose-dependent manner in addition to mRNA and protein expression.
"Once the expression of KLF4 is positively regulated by bile acids, even if the induction level is low, the self-replication mechanism induces a higher expression of KLF4," say Kazumori et al.
Examination the KLF4 promoter region revealed that the nuclear factor (NF)-κB binding site was responsible for bile acid-induced activation of the KLF4 promoter. Furthermore, KLF4 and Cdx2 were found to stimulate each other by binding directly to the promoter of the other.
Lastly, when the team transfected esophageal squamous epithelial cells with a KLF4 expression vector, they found that these cells began producing MUC2 protein.
"The results of the present experiments suggest that KLF4 is an important molecular mediator in the development of Barrett's epithelium," conclude the authors in the journal Gut.
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By Ingrid Grasmo