m6A demethylation of NNMT in CAFs promotes gastric cancer progression by enhancing macrophage M2 polarization

IF 9.1 1区 医学 Q1 ONCOLOGY
Tsz Kin Mak , Kuan Li , Zidan Zhao , Kexin Wang , Leli Zeng , Qilang He , Weiqun Lu , Wei Chen , Yulong He , Jia Li , Changhua Zhang
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引用次数: 0

Abstract

Cancer associated fibroblasts (CAFs) are the predominant stromal cells in the tumor microenvironment of gastric cancer (GC), interacting with both immune and tumor cells to drive cancer progression. However, the precise link between these interactions and their potential as therapeutic targets remains poorly understood. In this study, we identified for the first time that nicotinamide N-methyltransferase (NNMT) derived from CAFs promoted M2 macrophage polarization, which, in turn, facilitated the proliferation and migration of GC cells. Additionally, we discovered that NNMT expression in CAFs was regulated by the Fat mass and obesity related protein (FTO) via m6A demethylation. Both NNMT and FTO were highly expressed in tumor tissues and CAFs, with a positive correlation between FTO and NNMT levels in clinical samples. Mechanistically, FTO bound to NNMT mRNA, reducing m6A modification and enhancing NNMT expression. Knockdown of either NNMT or FTO in CAFs effectively inhibited M2 macrophage polarization and suppressed GC progression. These findings were validated in patient-derived organoid models and nude mouse models of GC. Collectively, our data revealed that FTO promoted M2 macrophage polarization by regulating the m6A demethylation of NNMT in CAFs, thereby driving GC progression. This identified a potential novel target for GC diagnosis and therapy.
cas中NNMT的m6A去甲基化通过增强巨噬细胞M2极化促进胃癌进展。
癌相关成纤维细胞(CAFs)是胃癌(GC)肿瘤微环境中的主要基质细胞,与免疫细胞和肿瘤细胞相互作用,驱动癌症进展。然而,这些相互作用与它们作为治疗靶点的潜力之间的确切联系仍然知之甚少。在本研究中,我们首次发现来自CAFs的烟酰胺n -甲基转移酶(NNMT)促进M2巨噬细胞极化,从而促进GC细胞的增殖和迁移。此外,我们发现NNMT在cas中的表达通过m6A去甲基化受到脂肪质量和肥胖相关蛋白(FTO)的调节。NNMT和FTO在肿瘤组织和CAFs中均高表达,临床样品中FTO与NNMT水平呈正相关。机制上,FTO结合NNMT mRNA,减少m6A修饰,增强NNMT表达。在cas中,NNMT或FTO的下调均能有效抑制M2巨噬细胞的极化,抑制GC的进展。这些发现在患者来源的类器官模型和裸鼠GC模型中得到了验证。总的来说,我们的数据显示,FTO通过调节cas中NNMT的m6A去甲基化来促进M2巨噬细胞极化,从而推动GC的进展。这为胃癌的诊断和治疗确定了一个潜在的新靶点。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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