Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease
Advanced, metastatic colorectal cancer (CRC) is associated with high rate of mortality because of its poor responsiveness to chemotherapy/immunotherapy. Recent studies have shown that hepcidin, a peptide hormone produced mainly by hepatocytes, is expressed by and enhances the growth of tumor cells....
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/21/5294 |
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| author | Antonio Di Grazia Davide Di Fusco Eleonora Franzè Marco Colella Georgios Strimpakos Silvia Salvatori Vincenzo Formica Federica Laudisi Claudia Maresca Alfredo Colantoni Angela Ortenzi Carmine Stolfi Ivan Monteleone Giovanni Monteleone |
| author_facet | Antonio Di Grazia Davide Di Fusco Eleonora Franzè Marco Colella Georgios Strimpakos Silvia Salvatori Vincenzo Formica Federica Laudisi Claudia Maresca Alfredo Colantoni Angela Ortenzi Carmine Stolfi Ivan Monteleone Giovanni Monteleone |
| author_sort | Antonio Di Grazia |
| collection | DOAJ |
| description | Advanced, metastatic colorectal cancer (CRC) is associated with high rate of mortality because of its poor responsiveness to chemotherapy/immunotherapy. Recent studies have shown that hepcidin, a peptide hormone produced mainly by hepatocytes, is expressed by and enhances the growth of tumor cells. We here assessed whether hepcidin expression helps identify subsets of CRC with advanced and aggressive course. By integrating results of in vitro/ex vivo studies with data of bioinformatics databases, we initially showed that hepcidin RNA and protein expression was more pronounced in tissue samples taken from the tumor area, as compared to the macroscopically unaffected, adjacent, colonic mucosa of CRC patients. The induction of hepcidin in the colonic epithelial cell line HCEC-1ct by interleukin (IL)-6, IL-21 and IL-23 occurred via a Stat3-dependent mechanism and, in primary CRC cells, hepcidin co-localized with active Stat3. In CRC tissue, hepcidin content correlated mainly with macrophage accumulation and IL-10 and CD206 expression, two markers of regulatory macrophages. Consistently, both IL-10 and CD206 were up-regulated by hepcidin in blood mononuclear cells. The highest levels of hepcidin were found in metastatic CRC and survival analysis showed that high expression of hepcidin associated with poor prognosis. Moreover, hepcidin expression correlated with markers of epithelial-to-mesenchymal transition and the silencing of hepcidin in CRC cells reduced epithelial-to-mesenchymal transition markers. These findings indicate that hepcidin is markedly induced in the advanced stages of CRC and suggest that it could serve as a prognostic biomarker in CRC. |
| first_indexed | 2024-03-09T19:11:55Z |
| format | Article |
| id | doaj.art-1005562ebb50488f92beeceea030e73f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T19:11:55Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-1005562ebb50488f92beeceea030e73f2023-11-24T04:02:09ZengMDPI AGCancers2072-66942022-10-011421529410.3390/cancers14215294Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the DiseaseAntonio Di Grazia0Davide Di Fusco1Eleonora Franzè2Marco Colella3Georgios Strimpakos4Silvia Salvatori5Vincenzo Formica6Federica Laudisi7Claudia Maresca8Alfredo Colantoni9Angela Ortenzi10Carmine Stolfi11Ivan Monteleone12Giovanni Monteleone13Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyInstitute of Biochemistry and Cell Biology (IBBC), National Council of Research (CNR), 00146 Rome, ItalyGastroenterology Unit, Fondazione Policlinico “Tor Vergata”, 00133 Rome, ItalyMedical Oncology Unit, Fondazione Policlinico “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, ItalyAdvanced, metastatic colorectal cancer (CRC) is associated with high rate of mortality because of its poor responsiveness to chemotherapy/immunotherapy. Recent studies have shown that hepcidin, a peptide hormone produced mainly by hepatocytes, is expressed by and enhances the growth of tumor cells. We here assessed whether hepcidin expression helps identify subsets of CRC with advanced and aggressive course. By integrating results of in vitro/ex vivo studies with data of bioinformatics databases, we initially showed that hepcidin RNA and protein expression was more pronounced in tissue samples taken from the tumor area, as compared to the macroscopically unaffected, adjacent, colonic mucosa of CRC patients. The induction of hepcidin in the colonic epithelial cell line HCEC-1ct by interleukin (IL)-6, IL-21 and IL-23 occurred via a Stat3-dependent mechanism and, in primary CRC cells, hepcidin co-localized with active Stat3. In CRC tissue, hepcidin content correlated mainly with macrophage accumulation and IL-10 and CD206 expression, two markers of regulatory macrophages. Consistently, both IL-10 and CD206 were up-regulated by hepcidin in blood mononuclear cells. The highest levels of hepcidin were found in metastatic CRC and survival analysis showed that high expression of hepcidin associated with poor prognosis. Moreover, hepcidin expression correlated with markers of epithelial-to-mesenchymal transition and the silencing of hepcidin in CRC cells reduced epithelial-to-mesenchymal transition markers. These findings indicate that hepcidin is markedly induced in the advanced stages of CRC and suggest that it could serve as a prognostic biomarker in CRC.https://www.mdpi.com/2072-6694/14/21/5294type 2 macrophagescancer metastasisprognosisStat3cytokines |
| spellingShingle | Antonio Di Grazia Davide Di Fusco Eleonora Franzè Marco Colella Georgios Strimpakos Silvia Salvatori Vincenzo Formica Federica Laudisi Claudia Maresca Alfredo Colantoni Angela Ortenzi Carmine Stolfi Ivan Monteleone Giovanni Monteleone Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease Cancers type 2 macrophages cancer metastasis prognosis Stat3 cytokines |
| title | Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease |
| title_full | Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease |
| title_fullStr | Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease |
| title_full_unstemmed | Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease |
| title_short | Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease |
| title_sort | hepcidin upregulation in colorectal cancer associates with accumulation of regulatory macrophages and epithelial mesenchymal transition and correlates with progression of the disease |
| topic | type 2 macrophages cancer metastasis prognosis Stat3 cytokines |
| url | https://www.mdpi.com/2072-6694/14/21/5294 |
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