Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice.
Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS). Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk.
School of Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, Fremantle, Western Australia, Australia ; Western Australian Institute for Medical Research, Perth, Western Australia, Australia.
Anita C G
AC
Chua
Borut R S
BR
Klopcic
Desiree S
DS
Ho
S Kristine
SK
Fu
Cynthia H
CH
Forrest
Kevin D
KD
Croft
John K
JK
Olynyk
Ian C
IC
Lawrance
Debbie
D
Trinder
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D019266:Iron, Dietary / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D016264:Dextran Sulfate; D017370:Interleukin-11; D015850:Interleukin-6; D019266:Iron, Dietary; D011990:Receptors, Transferrin; D050796:STAT3 Transcription Factor; D000099236:Solute Carrier Family 11, Member 2; C480029:Tfrc protein, mouse