N6-甲基腺苷甲基化调控 Epstein-Barr 病毒相关胃癌的肿瘤微环境

IF 2.5 4区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY World Journal of Gastrointestinal Oncology Pub Date : 2024-06-15 DOI:10.4251/wjgo.v16.i6.2555
Yu Zhang, Fang Zhou, Ming-Yu Zhang, Lijuan Feng, Jialun Guan, Ruonan Dong, Yujie Huang, S. Xia, JiaFu Liao, Kai Zhao
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We hypothesized EBV and m6A methylation regulators interact with each other in EBVaGC to differentiate it from other types of GC.\n AIM\n To investigate the mechanisms of m6A methylation regulators in EBVaGC to determine the differentiating factors from other types of GC.\n METHODS\n First, The Cancer Gene Atlas and Gene Expression Omnibus databases were used to analyze the expression pattern of m6A methylation regulators between EBVaGC and EBV-negative GC (EBVnGC). Second, we identified Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment of m6A-related differentially expressed genes. We quantified the relative abundance of immune cells and inflammatory factors in the tumor microenvironment (TME). Finally, cell counting kit-8 cell proliferation test, transwell test, and flow cytometry were used to verify the effect of insulin-like growth factor binding protein 1 (IGFBP1) in EBVaGC cell lines.\n RESULTS\n m6A methylation regulators were involved in the occurrence and development of EBVaGC. Compared with EBVnGC, the expression levels of m6A methylation regulators Wilms tumor 1-associated protein, RNA binding motif protein 15B, CBL proto-oncogene like 1, leucine rich pentatricopeptide repeat containing, heterogeneous nuclear ribonucleoprotein A2B1, IGFBP1, and insulin-like growth factor 2 binding protein 1 were significantly downregulated in EBVaGC (P < 0.05). The overall survival rate of EBVaGC patients with a lower expression level of IGFBP1 was significantly higher (P = 0.046). GO and KEGG functional enrichment analyses showed that the immunity pathways were significantly activated and rich in immune cell infiltration in EBVaGC. Compared with EBVnGC, the infiltration of activated CD4+ T cells, activated CD8+ T cells, monocytes, activated dendritic cells, and plasmacytoid dendritic cells were significantly upregulated in EBVaGC (P < 0.001). In EBVaGC, the expression level of proinflammatory factors interleukin (IL)-17, IL-21, and interferon-γ and immunosuppressive factor IL-10 were significantly increased (P < 0.05). In vitro experiments demonstrated that the expression level of IGFBP1 was significantly lower in an EBVaGC cell line (SNU719) than in an EBVnGC cell line (AGS) (P < 0.05). IGFBP1 overexpression significantly attenuated proliferation and migration and promoted the apoptosis levels in SNU719. Interfering IGFBP1 significantly promoted proliferation and migration and attenuated the apoptosis levels in AGS.\n CONCLUSION\n m6A regulators could remodel the TME of EBVaGC, which is classified as an immune-inflamed phenotype and referred to as a “hot” tumor. 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引用次数: 0

摘要

背景 N6-甲基腺苷(m6A)甲基化修饰存在于 Epstein-Barr 病毒(EBV)的原发感染、潜伏期和淋病再活化过程中。它还能修饰 EBV 潜伏基因和溶解基因。EBV 相关性胃癌(EBVaGC)是一种独特的胃癌分子亚型。我们假设 EBV 和 m6A 甲基化调节因子在 EBVaGC 中相互影响,从而将其与其他类型的胃癌区分开来。目的 研究 m6A 甲基化调节因子在 EBVaGC 中的作用机制,以确定与其他类型 GC 的区分因素。方法 首先,利用癌症基因图谱和基因表达总库数据库分析 EBVaGC 和 EBV 阴性 GC(EBVnGC)中 m6A 甲基化调节因子的表达模式。其次,我们确定了基因本体(GO)和京都基因组百科全书(KEGG)中与 m6A 相关的差异表达基因的功能富集。我们量化了肿瘤微环境(TME)中免疫细胞和炎症因子的相对丰度。最后,我们使用细胞计数试剂盒-8 细胞增殖试验、透孔试验和流式细胞术验证了胰岛素样生长因子结合蛋白 1 (IGFBP1) 在 EBVaGC 细胞系中的作用。结果 m6A 甲基化调节因子参与了 EBVaGC 的发生和发展。与 EBVnGC 相比,m6A 甲基化调节因子 Wilms tumor 1-associated protein、RNA binding motif protein 15B、CBL proto-oncogene like 1、leucine rich pentatricopeptide repeat containing、heterogeneous nuclear ribonucleoprotein A2B1、IGFBP1 和 insulin-like growth factor 2 binding protein 1 在 EBVaGC 中的表达水平显著下调(P < 0.05)。IGFBP1表达水平较低的EBVaGC患者的总生存率明显较高(P = 0.046)。GO和KEGG功能富集分析表明,在EBVaGC中,免疫通路被明显激活,免疫细胞浸润丰富。与 EBVnGC 相比,EBVaGC 中活化的 CD4+ T 细胞、活化的 CD8+ T 细胞、单核细胞、活化的树突状细胞和浆细胞树突状细胞的浸润明显上调(P < 0.001)。在 EBVaGC 中,促炎因子白细胞介素(IL)-17、IL-21、干扰素-γ 和免疫抑制因子 IL-10 的表达水平明显升高(P < 0.05)。体外实验表明,IGFBP1 在 EBVaGC 细胞系(SNU719)中的表达水平明显低于 EBVnGC 细胞系(AGS)(P < 0.05)。在 SNU719 细胞中,IGFBP1 的过表达明显抑制了细胞的增殖和迁移,促进了细胞的凋亡。干扰 IGFBP1 能明显促进 AGS 的增殖和迁移,降低其凋亡水平。结论 m6A调节因子可重塑EBVaGC的TME,EBVaGC被归类为免疫炎症表型,被称为 "热 "肿瘤。在这些调节因子中,我们发现 IGFBP1 会影响增殖、迁移和凋亡。
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N6-methyladenosine methylation regulates the tumor microenvironment of Epstein-Barr virus-associated gastric cancer
BACKGROUND N6-methyladenosine (m6A) methylation modification exists in Epstein-Barr virus (EBV) primary infection, latency, and lytic reactivation. It also modifies EBV latent genes and lytic genes. EBV-associated gastric cancer (EBVaGC) is a distinctive molecular subtype of GC. We hypothesized EBV and m6A methylation regulators interact with each other in EBVaGC to differentiate it from other types of GC. AIM To investigate the mechanisms of m6A methylation regulators in EBVaGC to determine the differentiating factors from other types of GC. METHODS First, The Cancer Gene Atlas and Gene Expression Omnibus databases were used to analyze the expression pattern of m6A methylation regulators between EBVaGC and EBV-negative GC (EBVnGC). Second, we identified Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment of m6A-related differentially expressed genes. We quantified the relative abundance of immune cells and inflammatory factors in the tumor microenvironment (TME). Finally, cell counting kit-8 cell proliferation test, transwell test, and flow cytometry were used to verify the effect of insulin-like growth factor binding protein 1 (IGFBP1) in EBVaGC cell lines. RESULTS m6A methylation regulators were involved in the occurrence and development of EBVaGC. Compared with EBVnGC, the expression levels of m6A methylation regulators Wilms tumor 1-associated protein, RNA binding motif protein 15B, CBL proto-oncogene like 1, leucine rich pentatricopeptide repeat containing, heterogeneous nuclear ribonucleoprotein A2B1, IGFBP1, and insulin-like growth factor 2 binding protein 1 were significantly downregulated in EBVaGC (P < 0.05). The overall survival rate of EBVaGC patients with a lower expression level of IGFBP1 was significantly higher (P = 0.046). GO and KEGG functional enrichment analyses showed that the immunity pathways were significantly activated and rich in immune cell infiltration in EBVaGC. Compared with EBVnGC, the infiltration of activated CD4+ T cells, activated CD8+ T cells, monocytes, activated dendritic cells, and plasmacytoid dendritic cells were significantly upregulated in EBVaGC (P < 0.001). In EBVaGC, the expression level of proinflammatory factors interleukin (IL)-17, IL-21, and interferon-γ and immunosuppressive factor IL-10 were significantly increased (P < 0.05). In vitro experiments demonstrated that the expression level of IGFBP1 was significantly lower in an EBVaGC cell line (SNU719) than in an EBVnGC cell line (AGS) (P < 0.05). IGFBP1 overexpression significantly attenuated proliferation and migration and promoted the apoptosis levels in SNU719. Interfering IGFBP1 significantly promoted proliferation and migration and attenuated the apoptosis levels in AGS. CONCLUSION m6A regulators could remodel the TME of EBVaGC, which is classified as an immune-inflamed phenotype and referred to as a “hot” tumor. Among these regulators, we demonstrated that IGFBP1 affected proliferation, migration, and apoptosis.
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来源期刊
World Journal of Gastrointestinal Oncology
World Journal of Gastrointestinal Oncology Medicine-Gastroenterology
CiteScore
4.20
自引率
3.30%
发文量
1082
期刊介绍: The World Journal of Gastrointestinal Oncology (WJGO) is a leading academic journal devoted to reporting the latest, cutting-edge research progress and findings of basic research and clinical practice in the field of gastrointestinal oncology.
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