Hypoxia-inducible factor-2α activation promotes colorectal cancer progression by dysregulating iron homeostasis.

Abstract

Hypoxia-inducible factor (HIF), a key modulator of the transcriptional response to hypoxia, is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. In this study, we found that intestinal epithelium-specific disruption of the von Hippel-Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apc(min/+) intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and HIF-2α. Activation of HIF signaling resulted in increased cell survival in normal colon tissue; however, tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apc(min/+) mice in which HIF-2α was activated in the intestine. Consistent with this result, bromodeoxyuridine incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis showed that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2α-mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings show that a chronic increase in HIF-2α in the colon initiates protumorigenic signaling, which may have important implications in developing preventive and therapeutic strategies for colon cancer.

• Authors: Xiang Xue, Matthew Taylor, Erik Anderson, Cathy Hao, Aijuan Qu, Joel K Greenson, Ellen M Zimmermann, Frank J Gonzalez, Yatrik M Shah
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 9 Pg. 2285-93 (May 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22419665 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR

Chemical References

• Adenomatous Polyposis Coli Protein
• Basic Helix-Loop-Helix Transcription Factors
• Cation Transport Proteins
• Iron, Dietary
• solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
• endothelial PAS domain-containing protein 1
• Iron

Topics

• Adenomatous Polyposis Coli Protein (genetics)
• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Cation Transport Proteins (metabolism)
• Cell Growth Processes (physiology)
• Cell Survival (physiology)
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Disease Progression
• Female
• HCT116 Cells
• Homeostasis
• Humans
• Iron (metabolism)
• Iron, Dietary (administration & dosage)
• Male
• Mice
• Mice, Transgenic
• Mutation