| First Author | Darsigny M | Year | 2010 |
| Journal | Cancer Res | Volume | 70 |
| Issue | 22 | Pages | 9423-33 |
| PubMed ID | 21062980 | Mgi Jnum | J:166855 |
| Mgi Id | MGI:4849891 | Doi | 10.1158/0008-5472.CAN-10-1697 |
| Citation | Darsigny M, et al. (2010) Hepatocyte nuclear factor-4alpha promotes gut neoplasia in mice and protects against the production of reactive oxygen species. Cancer Res 70(22):9423-33 |
| abstractText | Hepatocyte nuclear factor-4alpha (Hnf4alpha) is a transcription factor that controls epithelial cell polarity and morphogenesis. Hnf4alpha 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 Hnf4alpha does not act as a tumor-suppressor gene but is crucial in promoting gut tumorigenesis in mice. Polyp multiplicity in ApcMin mice lacking Hnf4alpha is suppressed compared with littermate ApcMin controls. Analysis of microarray gene expression profiles from mice lacking Hnf4alpha 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 HNF4alpha 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 HNF4alpha 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 HNF4alpha as a potential therapeutic target to eradicate aberrant epithelial cell resistance to ROS production during intestinal tumorigenesis. |
