Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution (Wannan Medical College), Wuhu, China.
Department of Gastroenterology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, China.
J Immunother Cancer. 2021 Feb;9(2). doi: 10.1136/jitc-2020-001364.
The activation of tumor-associated macrophages (TAMs) facilitates the progression of gastric cancer (GC). Cell metabolism reprogramming has been shown to play a vital role in the polarization of TAMs. However, the role of methionine metabolism in function of TAMs remains to be explored.
Monocytes/macrophages were isolated from peripheral blood, tumor tissues or normal tissues from healthy donors or patients with GC. The role of methionine metabolism in the activation of TAMs was evaluated with both in vivo analyses and in vitro experiments. Pharmacological inhibition of the methionine cycle and modulation of key metabolic genes was employed, where molecular and biological analyses were performed.
TAMs have increased methionine cycle activity that are mainly attributed to elevated methionine adenosyltransferase II alpha (MAT2A) levels. MAT2A modulates the activation and maintenance of the phenotype of TAMs and mediates the upregulation of RIP1 by increasing the histone H3K4 methylation (H3K4me3) at its promoter regions.
Our data cast light on a novel mechanism by which methionine metabolism regulates the anti-inflammatory functions of monocytes in GC. MAT2A might be a potential therapeutic target for cancer cells as well as TAMs in GC.
肿瘤相关巨噬细胞（TAMs）的激活促进了胃癌（GC）的进展。细胞代谢重编程已被证明在 TAMs 的极化中起着至关重要的作用。然而，蛋氨酸代谢在 TAMs 功能中的作用仍有待探索。
从外周血、肿瘤组织或健康供体或 GC 患者的正常组织中分离单核细胞/巨噬细胞。通过体内分析和体外实验评估蛋氨酸代谢在 TAMs 激活中的作用。采用蛋氨酸循环的药理学抑制和关键代谢基因的调节，并进行分子和生物学分析。
TAMs 具有增加的蛋氨酸循环活性，主要归因于升高的蛋氨酸腺苷转移酶 IIα（MAT2A）水平。MAT2A 调节 TAMs 的激活和维持，并通过增加其启动子区域的组蛋白 H3K4 甲基化（H3K4me3）来上调 RIP1。
我们的数据揭示了蛋氨酸代谢调节 GC 中单核细胞抗炎功能的新机制。MAT2A 可能是 GC 中癌细胞和 TAMs 的潜在治疗靶点。
