In silico analysis suggests disruption of interactions between HAMP from hepatocytes and SLC40A1 from macrophages in hepatocellular carcinoma

Abstract

Abstract Background Identification of factors associated with proliferation in the hepatocellular carcinoma (HCC) microenvironment aids in understanding the mechanisms of disease progression and provides druggable targets. Gene expression profiles of individual cells in HCC and para-carcinoma tissues can be effectively obtained using the single-cell RNA sequencing (scRNA-Seq) technique. Here, we aimed to identify proliferative hepatocytes from HCC and para-carcinoma tissues, detect differentially expressed genes between the two types of proliferative hepatocytes, and investigate their potential roles in aberrant proliferation. Results Two respective gene signatures for proliferative cells and hepatocytes were established and used to identify proliferative hepatocytes from HCC and para-carcinoma tissues based on scRNA-Seq data. Gene expression profiles between the two types of proliferative hepatocytes were compared. Overall, 40 genes were upregulated in proliferative hepatocytes from para-carcinoma tissue, whereas no upregulated genes were detected in those from HCC tissue. Twelve of the genes, including HAMP, were specifically expressed in the liver tissue. Based on previous reports, we found that HAMP modulates cell proliferation through interaction with its receptor SLC40A1. Comprehensive analysis of cells in HCC and para-carcinoma tissues revealed that: (1) HAMP is specifically expressed in hepatocytes and significantly downregulated in malignant hepatocytes; (2) a subset of macrophages expressing SLC40A1 and genes reacting to various infections is present in para-carcinoma but not in HCC tissue. We independently validated the findings with scRNA-Seq and large-scale tissue bulk RNA-Seq/microarray analyses. Conclusion HAMP was significantly downregulated in malignant hepatocytes. In addition, a subset of macrophages expressing SLC40A1 and genes reacting to various infections was absent in HCC tissue. These findings support the involvement of HAMP-SLC40A1 signaling in aberrant hepatocyte proliferation in the HCC microenvironment. The collective data from our in silico analysis provide novel insights into the mechanisms underlying HCC progression and require further validation with wet laboratory experiments.

Keywords

• Single-cell RNA sequencing
• Cell-type-specific genes
• Proliferative hepatocyte
• HAMP-SLC40A1 signaling