n6 -甲基腺苷调节的外泌体生物发生在胃癌腹膜转移中协调了免疫抑制的转移前生态位。

IF 20.1 1区 医学 Q1 ONCOLOGY
Song Li, Jianyuan Zhou, Shuang Wang, Qian Yang, Shulun Nie, Chunwang Ji, Xue Zhang, Shuhan Li, Xuanyu Zhou, Jiahui Chu, Xuehui Wu, Jianqiao Jiao, Ruitao Xu, Qian Xu, Miao Huang, Qiushi Wang, Liliang Dou, Qinqin Hu, Fan Jiang, Xin Dai, Zhaodi Nan, Xinyu Song, Di Zhang, Lian Liu
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引用次数: 0

摘要

背景:由于治疗方案有限,预后不良,胃癌腹膜转移在临床上具有挑战性。胃癌腹膜转移前的分子机制,即转移前生态位(PMN)及其与n6 -甲基腺苷(m6A)修饰的关系尚不清楚。方法:利用87例切除的胃癌组织和4个公开数据集,探讨甲基转移酶样3 (METTL3)表达与胃癌腹膜转移的关系。通过外泌体治疗或巨噬细胞修饰,在免疫功能小鼠模型中探讨了m6A、外泌体或巨噬细胞在PMN形成中的作用。通过质谱、RNA/miRNA测序、RNA免疫沉淀、双荧光素酶测定和细胞中ras相关蛋白RAB27A (RAB27A)的点突变,揭示了关键基因和调控机制。采用酶联免疫吸附试验、流式细胞术和细胞毒性试验评估巨噬细胞和t细胞功能。结果:METTL3在胃癌细胞中的过表达通过甲基化RAB27A mRNA A502碱基,通过其m6A“读取器”YTH n6 -甲基腺苷RNA结合蛋白F1 (YTHDF1)促进RAB27A的翻译,导致外泌体生物发生增加。miRNA-17-92集群富集在mettl3过表达的细胞源性外泌体中,并靶向SRC激酶信号抑制剂1 (SRCIN1)激活腹膜巨噬细胞中SRC原癌基因非受体酪氨酸激酶(SRC)信号。巨噬细胞激活使腹膜细胞因子产生向免疫抑制方向倾斜,升高白细胞介素(IL)-10和肿瘤坏死因子(TNF)的水平,降低IL-1和IL-6的水平。这些细胞因子的转移抑制T细胞增殖和细胞毒活性,从而产生免疫抑制性PMN并导致腹膜转移。临床样本证实了METTL3、巨噬细胞和腹膜转移之间的关联。结论:我们的研究确定了一种复杂的m6a调节的腹膜PMN发育机制,该机制是由外泌体促进的巨噬细胞介导的。这些对胃癌腹膜转移的认识为转化研究提供了有希望的方向。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
N6-methyladenosine-regulated exosome biogenesis orchestrates an immunosuppressive pre-metastatic niche in gastric cancer peritoneal metastasis.

Background: Gastric cancer peritoneal metastasis is clinically challenging, given the limited treatment options and poor prognosis. The molecular mechanisms that precede gastric cancer peritoneal metastasis, known as the pre-metastatic niche (PMN), and its relationship with N6-methyladenosine (m6A) modification remain unclear.

Methods: We used 87 resected gastric cancer tissues and 4 public datasets to explore the association between methyltransferase-like 3 (METTL3) expression and gastric cancer peritoneal metastasis. Roles of m6A, exosomes, or macrophages in PMN formation were explored in immunocompetent mouse models through exosome treatments or macrophage modifications. Key genes and regulatory mechanisms were uncovered using mass spectrometry, RNA/miRNA sequencing, RNA-immunoprecipitation, dual-luciferase assays, and point mutations in the ras-related protein Rab-27A (RAB27A) in cells. Macrophage and T-cell functions were assessed using enzyme-linked immunosorbent assay, flow cytometry, and cytotoxicity assays.

Results: METTL3 overexpression in gastric cancer cells enhanced RAB27A translation by methylating its mRNA A502 base, facilitated by its m6A "reader" YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), and led to increased exosome biogenesis. The miRNA-17-92 cluster was enriched in METTL3-overexpressed cell-derived exosomes and targeted SRC kinase signaling inhibitor 1 (SRCIN1) to activate SRC proto-oncogene, non-receptor tyrosine kinase (SRC) signaling in peritoneal macrophages. Macrophage activation skewed cytokine production towards an immunosuppressive profile in the peritoneum, elevating the levels of interleukin (IL)-10 and tumor necrosis factor (TNF) and reducing the levels of IL-1 and IL-6. These cytokine shifts inhibited T cell proliferation and cytotoxic activities, which created an immunosuppressive PMN and led to peritoneal metastasis. The association between METTL3, macrophages, and peritoneal metastasis was verified in clinical samples.

Conclusions: Our study identified an intricate m6A-regulated mechanism of peritoneal PMN development that is mediated by exosome-promoted macrophages. These insights into gastric cancer peritoneal metastasis offer promising directions for translational research.

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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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