Inflammatory bowel disease (IBD) is a chronic inflammatory disorder and is a major risk factor for colorectal cancer (CRC). Hypoxia is a feature of IBD and modulates cellular and mitochondrial metabolism. However, the role of hypoxic metabolism in IBD is unclear. Because mitochondrial dysfunction is an early hallmark of hypoxia and inflammation, an unbiased proteomics approach was used to assess the mitochondria in a mouse model of colitis. Through this analysis, we identified a ferrireductase: six-transmembrane epithelial antigen of prostate 4 (STEAP4) was highly induced in mouse models of colitis and in IBD patients. STEAP4 was regulated in a hypoxia-dependent manner that led to a dysregulation in mitochondrial iron balance, enhanced reactive oxygen species production, and increased susceptibility to mouse models of colitis. Mitochondrial iron chelation therapy improved colitis and demonstrated an essential role of mitochondrial iron dysregulation in the pathogenesis of IBD. To address if mitochondrial iron dysregulation is a key mechanism by which inflammation impacts colon tumorigenesis, STEAP4 expression, function, and mitochondrial iron chelation were assessed in a colitis-associated colon cancer model (CAC). STEAP4 was increased in human CRC and predicted poor prognosis. STEAP4 and mitochondrial iron increased tumor number and burden in a CAC model. These studies demonstrate the importance of mitochondrial iron homeostasis in IBD and CRC.
Proceedings of the National Academy of Sciences of the United States of America. 2017 Oct 23 [Epub ahead of print]
Xiang Xue, Bryce X Bredell, Erik R Anderson, Angelical Martin, Christopher Mays, Hiroko Nagao-Kitamoto, Sha Huang, Balázs Győrffy, Joel K Greenson, Karin Hardiman, Jason R Spence, Nobuhiko Kamada, Yatrik M Shah
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; ., Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109., Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109., Momentum Cancer Biomarker Research Group, Research Center for Natural Sciences, Institute of Enzymology, Hungarian Academy of Sciences, Budapest 1117, Hungary., Department of Pathology, University of Michigan, Ann Arbor, MI 48109., Department of Surgery, University of Michigan, Ann Arbor, MI 48109.