Wu Dehai, Liang Shuhang, Guo Hongrui, Zhang Shugeng, Yang Guangchao, Yuan Yubin, Liu Lianxin
Department of Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of General Surgery, Heze Municipal Hospital, Heze, China.
Front Genet. 2022 Jan 31;12:790093. doi: 10.3389/fgene.2021.790093. eCollection 2021.
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.
由MARC1、MARC2、CYB5和CYB5R组成的N-还原酶系统（NRES）负责N-氧化化合物的还原，并参与多种生理过程。例如，MARC2是一种重要的预后指标，在肝细胞癌中表达下调，MARC2的下调对脂质代谢和细胞周期进程的调节至关重要。然而，MARC2在肿瘤免疫微环境改变中的作用此前尚未得到研究。在本研究中，我们发现MARC2的下调与CD4+T细胞分化为调节性T细胞（Tregs）有关。此外，恢复MARC2的表达可通过PPARA相关的脂质代谢信号通路增加HLA-C和B2M的表达，这有助于将肿瘤抗原呈递给肿瘤浸润性T细胞。此外，MARC2的表达与多个免疫检查点呈负相关。基于28个与MARC2相关的免疫检查点产生免疫检查点负担。免疫检查点负担较高的患者预计预后较差，活化的CD8 T细胞水平较低。结果表明，NRES的表达是肝细胞癌的预后指标，MARC2对预测预后有显著贡献。最后，发现肝癌患者中MARC2的缺失促进免疫逃逸并与免疫抑制相关。
