Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial-Mesenchymal Transition and Correlates with Progression of the Disease.
Antonio Di GraziaDavide Di FuscoEleonora FranzèMarco ColellaGeorgios StrimpakosSilvia SalvatoriVincenzo FormicaFederica LaudisiClaudia MarescaAlfredo ColantoniAngela OrtenziCarmine StolfiIvan MonteleoneGiovanni MonteleonePublished in: Cancers (2022)
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.
Keyphrases
- poor prognosis
- iron deficiency
- induced apoptosis
- long non coding rna
- epithelial mesenchymal transition
- squamous cell carcinoma
- cell proliferation
- end stage renal disease
- computed tomography
- cell cycle arrest
- transcription factor
- radiation therapy
- oxidative stress
- binding protein
- newly diagnosed
- peripheral blood
- artificial intelligence
- locally advanced
- endothelial cells
- peritoneal dialysis
- deep learning
- big data
- metastatic colorectal cancer
- rectal cancer
- stress induced