Objective Fat mass and obesity-associated protein (FTO), an eraser of N 6-methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown. Design The functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment. Results FTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumour-infiltrating CD8+ T cells. Furthermore, we identified GPNMB to be a downstream target of FTO, which reduced the m6A abundance of GPNMB, hence, stabilising it from degradation by YTH N 6-methyladenosine RNA binding protein F2. Of note, GPNMB was packaged into sEVs derived from HCC cells and bound to the surface receptor SDC4 of CD8+ T cells, resulting in the inhibition of CD8+ T cell activation. A potential FTO inhibitor, CS2, suppresses the oncogenic functions of HCC cells and enhances the sensitivity of anti-PD-1 and sorafenib treatment. Conclusion Targeting the FTO/m6A/GPNMB axis could significantly suppress tumour growth and metastasis, and enhance immune activation, highlighting the potential of targeting FTO signalling with effective inhibitors for HCC therapy. All data relevant to the study are included in the article or uploaded as supplementary information.

中文翻译：

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靶向致癌 m6A 去甲基化酶 FTO 抑制肝细胞癌的肿瘤发生并增强免疫反应


目的 脂肪量和肥胖相关蛋白 （FTO） 是 N 6-甲基腺苷 （m6A） 的擦除蛋白，在各种癌症中起致癌作用。然而，它在肝细胞癌 （HCC） 中的作用尚不清楚。此外，小细胞外囊泡 （sEVs 或外泌体） 是肿瘤发生和转移的关键介质，但 FTO 介导的 m6A 修饰与 HCC 中 sEV 之间的关系尚不清楚。设计 在体外和体内研究了 FTO 和糖蛋白非转移性黑色素瘤蛋白 B （GPNMB） 在 HCC 进展中的功能和机制。syndecan-4 中和抗体 （SDC4） 用于评估 sEV-GPNMB 的意义。FTO 抑制剂 CS2 用于检查对抗 PD-1 和索拉非尼治疗的影响。结果 FTO 在患者 HCC 肿瘤中的表达上调。在功能上，FTO 在体外促进 HCC 细胞增殖、迁移和侵袭，在体内促进肿瘤生长和转移。FTO 敲低增强了肿瘤浸润 CD8+ T 细胞的激活和募集。此外，我们发现 GPNMB 是 FTO 的下游靶标，它降低了 GPNMB 的 m6A 丰度，从而稳定了它免受 YTH N 6-甲基腺苷 RNA 结合蛋白 F2 的降解。值得注意的是，GPNMB 被包装到源自 HCC 细胞的 sEV 中，并与 CD8+ T 细胞的表面受体 SDC4 结合，从而抑制 CD8+ T 细胞活化。一种潜在的 FTO 抑制剂 CS2 抑制 HCC 细胞的致癌功能，并增强抗 PD-1 和索拉非尼治疗的敏感性。结论 靶向 FTO/m6A/GPNMB 轴可显著抑制肿瘤生长和转移，增强免疫激活，凸显了以有效抑制剂靶向 FTO 信号传导治疗 HCC 的潜力。 与研究相关的所有数据都包含在文章中或作为补充信息上传。