Department of Plastic and Aesthetic Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Cell Death Dis. 2022 Jan 10;13(1):32. doi: 10.1038/s41419-021-04345-9.
Macrophage-derived exosomes (Mφ-Exo) have multidimensional involvement in tumor initiation, progression, and metastasis, but their regulation in hepatocellular carcinoma (HCC) is not fully understood. RBPJ has been implicated in macrophage activation and plasticity. In this study we assess the role of exosomes derived from RBPJ-overexpressed macrophages (RBPJ Mφ-Exo) in HCC. The circular RNA (circRNA) profiles in RBPJ Mφ-Exo and THP-1-like macrophages (WT Mφ)-Exo was evaluated using circRNA microarray. CCK-8, Transwell, and flow cytometry analyses were used to evaluate the function of Mφ-Exo-circRNA on HCC cells. Luciferase reporter assays, RNA immunoprecipitation, and Pearson's correlation analysis were used to confirm interactions. A nude mouse xenograft model was used to further analyze the functional significance of Mφ-Exo-cirRNA in vivo. Our results shown that hsa_circ_0004658 is upregulated in RBPJ Mφ-Exo compared to WT Mφ-Exo. RBPJ Mφ-Exo and hsa_circ_0004658 inhibits proliferation and promotes apoptosis in HCC cells, whereas hsa_circ_0004658 knockdown stimulated cell proliferation and migration but restrained apoptosis in vitro and promotes tumor growth in vivo. The effects of RBPJ Mφ-Exo on HCC cells can be reversed by the hsa_circ_0004658 knockdown. Mechanistic investigations revealed that hsa_circ_0004658 acts as a ceRNA of miR-499b-5p, resulting in the de-repression of JAM3. These results indicate that exosome circRNAs secreted from RBPJ Mφ inhibits tumor progression through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway and hsa_circ_0004658 may be a diagnostic biomarker and potential target for HCC therapy.
巨噬细胞衍生的外泌体 (Mφ-Exo) 在肿瘤的发生、发展和转移中具有多维作用，但它们在肝细胞癌 (HCC) 中的调控机制尚不完全清楚。RBPJ 已被牵连到巨噬细胞的激活和可塑性中。在这项研究中，我们评估了 RBPJ 过表达的巨噬细胞衍生的外泌体 (RBPJ Mφ-Exo) 在 HCC 中的作用。使用环状 RNA (circRNA) 微阵列评估了 RBPJ Mφ-Exo 和 THP-1 样巨噬细胞 (WT Mφ)-Exo 的 circRNA 图谱。CCK-8、Transwell 和流式细胞术分析用于评估 Mφ-Exo-circRNA 对 HCC 细胞的功能。荧光素酶报告基因检测、RNA 免疫沉淀和 Pearson 相关分析用于证实相互作用。裸鼠异种移植模型用于进一步分析 Mφ-Exo-cirRNA 在体内的功能意义。我们的结果表明，与 WT Mφ-Exo 相比，hsa_circ_0004658 在 RBPJ Mφ-Exo 中上调。RBPJ Mφ-Exo 和 hsa_circ_0004658 抑制 HCC 细胞的增殖并促进其凋亡，而 hsa_circ_0004658 敲低则在体外刺激细胞增殖和迁移，但抑制凋亡，并促进体内肿瘤生长。RBPJ Mφ-Exo 对 HCC 细胞的影响可以通过 hsa_circ_0004658 的敲低来逆转。机制研究表明，hsa_circ_0004658 作为 miR-499b-5p 的 ceRNA，导致 JAM3 的去抑制。这些结果表明，RBPJ Mφ 分泌的外泌体 circRNA 通过 hsa_circ_0004658/miR-499b-5p/JAM3 通路抑制肿瘤进展，hsa_circ_0004658 可能是 HCC 诊断的生物标志物和潜在治疗靶点。
