Abstract
The N-reductive enzyme system (NRES), composed of MARC1, MARC2, CYB5, and CYB5R, is responsible for the reduction of N-oxygenated compounds and participates in several physiological processes. For example, MARC2 serves as an important prognostic indicator and is downregulated in hepatocellular carcinoma, and the downregulation of MARC2 is critical to the regulation of lipid metabolism and cell cycle progression. However, the role of MARC2 in tumor immune microenvironment modification had not previously been investigated. In this study, we found that downregulation of MARC2 was associated with the differentiation of CD4+T cells into regulatory T cells (Tregs). Furthermore, restoring the expression of MARC2 could increase the expression of HLA-C and B2M via PPARA-related lipid metabolism signaling pathways, which could facilitate tumor antigen presentation to the tumor-infiltrating T cells. Additionally, MARC2 expression negatively correlated with several immune checkpoints. The immune checkpoint burden was generated based on 28 MARC2-related immune checkpoints. Patients with a higher immune checkpoint burden were predicted to have a poorer prognosis and a lower level of activated CD8+ T cells. The results showed that expression of the NRES is a prognostic indicator of hepatocellular carcinoma and MARC2 contributes significantly to predict the prognosis. Finally, loss of MARC2 in HCC patients was found to facilitate immune escape and was associated with immunosuppression.
Highlights
The N-reductive enzyme system (NRES), composed of MARC1, MARC2, CYB5, and CYB5R, is responsible for the reduction of N-oxygenated compounds (Wahl et al, 2010; Havemeyer et al, 2011)
The expression level of the NRES was derived from the ssGSEA (Gene set enrichment analysis) method based on the gene expression of MARC1, MARC2, CYB5A, CYB5B, CYB5R1, CYB5R2, CYB5R3, and CYB5R4
GSEA showed that the gene sets related to metabolic signaling pathways, such as xenobiotic metabolism, bile acid metabolism, and fatty acid metabolism were enriched in patients with higher levels of NRES expression, while the gene sets related to the immune signaling pathway, such as the T cell receptor signaling pathway and FC gamma R-mediated phagocytosis, were enriched in patients with lower levels of NRES expression (Figures 1G,H)
Summary
The N-reductive enzyme system (NRES), composed of MARC1, MARC2, CYB5, and CYB5R, is responsible for the reduction of N-oxygenated compounds (Wahl et al, 2010; Havemeyer et al, 2011). These compounds can be small, inorganic or organic molecules, with chemical bonds between nitrogen and oxygen participating in various functions. The NRES has been found to be involved in the regulation of lipid metabolism (Neve et al, 2012). MARC2 is important for N-oxygenation reduction and lipid metabolism (Neve et al, 2012). Our previous study verified that MARC2 expression inhibited the development of hepatocellular carcinoma (HCC) by elevating the expression of p27 (Wu et al, 2020)
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