Activation of hypoxia-inducible factor 2alpha promotes colorectal carcinogenesis

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	CANCER-26

* FARE Award Winner

Authors

• A Qu
• X Xiang
• M Taylor
• E Anderson
• YM Shah
• FJ Gonzalez

Abstract

Hypoxia-inducible factor (HIF) is critical for adaptive response to hypoxia and is increased in colon cancer. However, its role in colon carcinogenesis in vivo remains unclear. 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 Apcmin/+ tumor model. Intestinal disruption of Vhl increased colon tumor multiplicity and progression. These effects were ameliorated after double disruption of Vhl and Hif-2α. HIF activation 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 Apcmin/+ mice in which HIF-2α was activated in the intestine. Consistently, BrdU incorporation indicated increased cellular proliferation in colon tumors following HIF activation. Further analysis demonstrated that dysregulation of intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was critical for 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 demonstrate that a chronic increase in HIF-2α in the colon initiates pro-tumorigenic signaling which may have important implications in developing preventive and therapeutic strategies for colon cancer.

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