Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease

Abstract

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.

Managing the Dual Nature of Iron to Preserve Health

“…This homeostatic modulation of hepcidin regulates the amount of FPN1 on the cell surface and thus iron release from duodenal enterocytes, splenic macrophages, and hepatocytes. Although hepcidin is also expressed by other cell types, such as inflammatory macrophages [ 38 ], epidermal cells [ 39 ], dendritic cells [ 40 ], and some cancer cells [ 41 , 42 , 43 ], only hepatocyte-derived hepcidin exerts systemic control of body iron levels [ 44 ]. In other tissues, such as the heart, hepcidin has an important cell-autonomous function in regulating cardiomyocyte iron concentration [ 45 ].…”

Multifaceted Insights into Innovative Approaches to Treating Colorectal Cancer Metastasis: From Emerging Biological Factors to Radiomics

“…Di Grazia A. et al [ 1 ] directed their attention towards hepcidin, a peptide hormone primarily synthesized in the liver by hepatocytes, although it is also produced by macrophages and enterocytes. Hepcidin mainly controls the absorption of dietary iron in the intestines and the release of iron from storage in the liver and spleen.…”