title: Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis.
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.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sadeesh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Weisz
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Triner
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Liwei
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Durga
authors.initials: D
authors.lastname: Attili
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Pant
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest 1117, Hungary; 2nd Department of Pediatrics, Semmelweis University, Budapest 1085, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China.
authors.forename: Mingkun
authors.initials: M
authors.lastname: Zhan
authors.affiliation: 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.
authors.forename: Christin
authors.initials: C
authors.lastname: Carter-Su
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hardiman
authors.affiliation: 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.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Dame
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: James
authors.initials: J
authors.lastname: Varani
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Brenner
authors.affiliation: 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.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
authors.affiliation: 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.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000150:complications / Q000473:pathology; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016203:CDC2 Protein Kinase; D027682:Cation Transport Proteins; D007501:Iron; D053612:Janus Kinases; D050796:STAT3 Transcription Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2