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-supple...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
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Public Library of Science
2013
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| Online Access: | http://hdl.handle.net/20.500.11937/48254 |
| _version_ | 1848758058714398720 |
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| author | Chua, A. Klopcic, B. Ho, D. Fu, S.K. Forrest, C. Croft, K. Olynyk, John Lawrance, I. Trinder, D. |
| author_facet | Chua, A. Klopcic, B. Ho, D. Fu, S.K. Forrest, C. Croft, K. Olynyk, John Lawrance, I. Trinder, D. |
| author_sort | Chua, A. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T09:37:57Z |
| format | Journal Article |
| id | curtin-20.500.11937-48254 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T09:37:57Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-482542017-09-13T14:23:34Z Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice Chua, A. Klopcic, B. Ho, D. Fu, S.K. Forrest, C. Croft, K. Olynyk, John Lawrance, I. Trinder, D. 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. 2013 Journal Article http://hdl.handle.net/20.500.11937/48254 10.1371/journal.pone.0078850 Public Library of Science fulltext |
| spellingShingle | Chua, A. Klopcic, B. Ho, D. Fu, S.K. Forrest, C. Croft, K. Olynyk, John Lawrance, I. Trinder, D. Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice |
| title | Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice |
| title_full | Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice |
| title_fullStr | Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice |
| title_full_unstemmed | Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice |
| title_short | Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice |
| title_sort | dietary iron enhances colonic inflammation and il-6/il-11-stat3 signaling promoting colonic tumor development in mice |
| url | http://hdl.handle.net/20.500.11937/48254 |