title: 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.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.forename: Erik
authors.initials: E
authors.lastname: Anderson
authors.forename: Cathy
authors.initials: C
authors.lastname: Hao
authors.forename: Aijuan
authors.initials: A
authors.lastname: Qu
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Zimmermann
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D045325:HCT116 Cells; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019266:Iron, Dietary / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051792:Basic Helix-Loop-Helix Proteins; D027682:Cation Transport Proteins; D007501:Iron; D019266:Iron, Dietary; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2