骨骼是肝细胞癌（HCC）的次要转移部位。HCC患者骨转移会导致生活质量降低和生存时间缩短。细胞外囊泡（EVs）广泛参与了HCC的形成和转移。然而，初发HCC与EVs介导的骨病变之间的通讯仍不清楚，骨转移对HCC进展可能的影响仍然大多未知。在这里，发现骨转移HCC来源的EVs（BM-EVs）定位在同位移植HCC细胞上并促进HCC进展。从机理上讲，miR-3190-5p（miR-3190）在从骨骼病变中分离出的细胞内HCC细胞以及其衍生的EVs中上调。 BM-EVs中的miR-3190转移至同位移植的肿瘤细胞并通过下调AlkB同源物5（ALKBH5）表达增强其转移能力。 ALKBH5水平降低通过N6- 甲基腺苷依赖性和非依赖性的方式调节基因表达，加剧HCC的促转移特性。最后，带有HCC亲和力的拮抗物-miR-3190负载的脂质体成功抑制了接受BM-EVs治疗的小鼠中HCC的进展。这些发现揭示了BM-EVs通过转移ALKBH5靶向的miR-3190在同位移植HCC中启动促进转移的级联，并且miR-3190是在骨转移患者中抑制HCC进展的有前途的治疗靶点。 ©2023 The Authors. Advanced Science由Wiley-VCH GmbH出版。

Bone is the second leading metastatic site for hepatocellular carcinoma (HCC). Patients with HCC and bone metastasis suffer poor quality of life and reduced survival time. Extracellular vesicles (EVs) are widely involved in HCC formation and metastasis. However, the communication between primary HCC and bone lesions mediated by EVs remains unclear and the possible effect of bone metastasis on the progression of HCC remains largely unknown. Here, bone-metastasized HCC-derived EVs (BM-EVs) are found to localize to orthotropic HCC cells and promote HCC progression. Mechanistically, miR-3190-5p (miR-3190) is upregulated in intracellular HCC cells isolated from bone lesions as well as in their derived EVs. miR-3190 in BM-EVs is transferred into orthotopic tumor cells and enhances their metastatic capacity by downregulating AlkB homolog 5 (ALKBH5) expression. Decreased level of ALKBH5 exacerbates the prometastatic characteristics of HCC by modulating gene expression in N6-methyladenosine-dependent and -independent ways. Finally, antagomir-miR-3190-loaded liposomes with HCC affinity successfully suppress HCC progression in mice treated with BM-EVs. These findings reveal that BM-EVs initiate prometastatic cascades in orthotopic HCC by transferring ALKBH5-targeting miR-3190 and miR-3190 is serving as a promising therapeutic target for inhibiting the progression of HCC in patients with bone metastasis.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.