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Cell Metab. 2016 Sep 13;24(3):447-461. doi: 10.1016/j.cmet.2016.07.015. Epub 2016 Aug 18.

Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis.

Author information

1
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
2
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
3
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
4
MTA TTK Lendület Cancer Biomarker Research Group, Budapest 1117, Hungary; 2nd Department of Pediatrics, Semmelweis University, Budapest 1085, Hungary.
5
Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China.
6
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
7
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
8
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
9
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
10
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
11
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: shahy@umich.edu.

Abstract

Dietary iron intake and systemic iron balance are implicated in colorectal cancer (CRC) development, but the means by which iron contributes to CRC are unclear. Gene expression and functional studies demonstrated that the cellular iron importer, divalent metal transporter 1 (DMT1), is highly expressed in CRC through hypoxia-inducible factor 2α-dependent transcription. Colon-specific Dmt1 disruption resulted in a tumor-selective inhibitory effect of proliferation in mouse colon tumor models. Proteomic and genomic analyses identified an iron-regulated signaling axis mediated by cyclin-dependent kinase 1 (CDK1), JAK1, and STAT3 in CRC progression. A pharmacological inhibitor of DMT1 antagonized the ability of iron to promote tumor growth in a CRC mouse model and a patient-derived CRC enteroid orthotopic model. Our studies implicate a growth-promoting signaling network instigated by elevated intracellular iron levels in tumorigenesis, offering molecular insights into how a key dietary component may contribute to CRC.

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PMID:
27546461
PMCID:
PMC5023486
DOI:
10.1016/j.cmet.2016.07.015
[Indexed for MEDLINE]
Free PMC Article

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