Hepatocyte Nuclear Factor-4α Promotes Gut Neoplasia in Mice and Protects against the Production of Reactive Oxygen Species

Hepatocyte nuclear factor-4 alpha (Hnf4 alpha) is a transcription factor that controls epithelial cell polarity and morphogenesis. Hnf4 alpha conditional deletion during postnatal development has minor effects on intestinal epithelium integrity but promotes activation of the Wnt/beta-catenin pathway without causing tumorigenesis. Here, we show that Hnf4 alpha does not act as a tumor-suppressor gene but is crucial in promoting gut tumorigenesis in mice. Polyp multiplicity in Apc(Min) mice lacking Hnf4 alpha is suppressed compared with littermate Apc(Min) controls. Analysis of microarray gene expression profiles from mice lacking Hnf4 alpha in the intestinal epithelium identifies novel functions of this transcription factor in targeting oxidoreductase-related genes involved in the regulation of reactive oxygen species (ROS) levels. This role is supported with the demonstration that Hnf4 alpha is functionally involved in the protection against spontaneous and 5-fluorouracil chemotherapy-induced production of ROS in colorectal cancer cell lines. Analysis of a colorectal cancer patient cohort establishes that Hnf4 alpha is significantly upregulated compared with adjacent normal epithelial resections. Several genes involved in ROS neutralization are also induced in correlation with HNF4A expression. Altogether, the findings point to the nuclear receptor Hnf4 alpha as a potential therapeutic target to eradicate aberrant epithelial cell resistance to ROS production during intestinal tumorigenesis. Cancer Res; 70(22); 9423-33. (C) 2010 AACR.