Hepcidin Downregulation Correlates With Disease Aggressiveness And Immune Infiltration in Liver Cancers

Abstract

BackgroundHepcidin is a polypeptide hormone mainly produced by hepatocytes to modulate systemic iron balance. A drastic downregulation of the hepcidin gene was found in liver cancers. However, there is a paucity of information about the clinical significance of hepcidin gene downregulation in liver cancers.MethodsHepcidin expression profiles were assessed using multiple public datasets via several bioinformatics platforms. Clinical and pathological information was utilized to stratify patients for comparison. Patient survival outcomes were evaluated using the Kaplan-Meier plotter, a meta-analysis tool. Tumor immune infiltration was analyzed using the single sample gene set enrichment analysis (ssGSEA) approach on the Cancer Genome Atlas (TCGA) dataset. Hepcidin antagonist Fursultiamine was used to treat liver cancer HepG2 and Huh7 cells together with Sorafenib.ResultsHepcidin gene was predominantly expressed in benign liver tissues but drastically decreased in liver cancer tissues. Hepcidin reduction in liver cancers correlated with risk factors like non-alcoholic fatty liver disease (NAFLD) and liver fibrosis, as well as cancer grade and tumor stage. Hepcidin downregulation was associated with a rapid cancer progression and worse disease-specific survival, especially in patients of the White race without alcohol consumption history. Hepcidin expression in liver cancer tissues positively correlated with the bone morphogenetic protein-6 (BPM6)/interleukin-6 (IL6) cytokines and cytotoxic immune infiltration. Blocking hepcidin action with its antagonist Fursultiamine moderately reduced Sorafenib-induced apoptotic cell death in HepG2 and Huh7 cells.ConclusionHepcidin downregulation in liver cancers correlated with liver cancer risk factors, cancer aggressiveness, cytotoxic immune cell infiltration, and patient survival outcomes. BMP6/IL6 pathway insufficiency is a potential cause of hepcidin downregulation in liver cancers.

The Role of Iron in Cancer Progression

“…In addition, blocking hepcidin with its antagonist furthiomine could moderately reduce sorafenib-induced apoptosis in HepG2 and Huh7 cells (54). In consistent, HAMP, the coding gene for hepcidin is mainly expressed in benign liver tissues but significantly reduced in hepatocellular carcinoma tissues (54,55). Similarly, Z. Wang et al found that HAMP was decreased and associated with the chemokine CCL16 in Cholangiocarcinoma (CHOL), the second common malignant tumor in the liver, indicating that HAMP may contribute to the immune activation in CHOL microenvironment (56).…”

“…Furthermore, in patients of the White race with no history of alcohol consumption, down-regulation of hepcidin is associated with rapid cancer progression and poor disease-specific survival. Hepcidin expression is positively correlated with BMP6/interleukin -6 (IL6) cytokines and cytotoxic immune infiltration in liver cancer tissues ( 54 ). In addition, blocking hepcidin with its antagonist furthiomine could moderately reduce sorafenib-induced apoptosis in HepG2 and Huh7 cells ( 54 ).…”

“…Hepcidin expression is positively correlated with BMP6/interleukin -6 (IL6) cytokines and cytotoxic immune infiltration in liver cancer tissues ( 54 ). In addition, blocking hepcidin with its antagonist furthiomine could moderately reduce sorafenib-induced apoptosis in HepG2 and Huh7 cells ( 54 ). In consistent, HAMP , the coding gene for hepcidin is mainly expressed in benign liver tissues but significantly reduced in hepatocellular carcinoma tissues ( 54 , 55 ).…”

“…In addition, blocking hepcidin with its antagonist furthiomine could moderately reduce sorafenib-induced apoptosis in HepG2 and Huh7 cells ( 54 ). In consistent, HAMP , the coding gene for hepcidin is mainly expressed in benign liver tissues but significantly reduced in hepatocellular carcinoma tissues ( 54 , 55 ). Similarly, Z. Wang et al.…”

Prognostic and immunological potential of PPM1G in lung adenocarcinoma

“…The 600 genes highest correlated with PPM1G and the 100 related up-regulated genes correlated with the survival of LUAD were drawn into Venn diagram by the XIANTAO platform [23] (www.xiantao.love), and 29 intersection genes were obtained. We used DAVID [24] (http://david.ncifcrf.gov/) to enrich these genes via go and KEGG pathway analysis.…”