Hepatocyte-nuclear-factor-4a promotes gut neoplasia in mice and protects against the production of reactive oxygen species. Mus musculus

Hepatocyte-nuclear-factor-4α (Hnf4α) is a transcription factor that controls epithelial cell polarity and maturation during embryogenesis. Hnf4α conditional deletion during post-natal development results in minor consequences on intestinal epithelium integrity but promotes activation of the Wnt/β-catenin pathway. Here we show that Hnf4α does not act as a tumor suppressor gene but is crucial to promote gut tumorigenesis in mice. Polyp multiplicity in ApcMin mice that lacks Hnf4α is suppressed in comparison to littermate ApcMin controls. Analysis of microarray gene expression profiles from mice lacking Hnf4α in the intestinal epithelium identifies its novel function in regulating the expression of reactive oxygen species (ROS) detoxifying genes. This role is supported with the demonstration that HNF4α is functionally involved in the protection against spontaneous and 5-fluorouracil chemotherapy-induced production of intracellular ROS in colorectal cancer cell lines. The analysis of a colorectal cancer patient cohort establishes that HNF4α is significantly up-regulated at both gene transcript and protein levels in tumors relative to adjacent benign epithelial resections. Several genes involved in ROS neutralization are also up-regulated in correlation with HNF4α expression. All together, the findings point to the nuclear receptor HNF4α as a potential therapeutic target to eradicate aberrant epithelial cell resistance to ROS production during intestinal tumorigenesis. Overall design: HNF4alpha was conditionally knockout in the mouse epithelial intestine with the 12.4-kb VillinCRE. A total of 3 control and 3 mutant littermates individuals were sacrificed at 7 months of age. The distal jejunum was harvested and Total RNA was isolated from each individuals. Each RNA sample was independently used to generate probes to screen affymetrix chips.