Exosomal hsa_circ_0004658 derived from RBPJ overexpressed-macrophages inhibits hepatocellular carcinoma progression via miR-499b-5p/JAM3.
Exosomal hsa_circ_0004658 derived from RBPJ overexpressed-macrophages inhibits hepatocellular carcinoma progression via miR-499b-5p/JAM3.
复制标题
源自 RBPJ 过表达巨噬细胞的外泌体 hsa_circ_0004658 通过 miR-499b-5p/JAM3 抑制肝细胞癌进展
DOI：
10.1038/s41419-021-04345-9
复制
发表时间：
2022-01-10
影响因子：
9
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Zhang L;Zhang J;Li P;Li T;Zhou Z;Wu H
巨噬细胞来源的外切体(Mφ-Exo)参与了肿瘤的发生、发展和转移，但其在肝细胞癌中的调控机制尚不完全清楚。RBPJ与巨噬细胞的激活和可塑性有关。在这项研究中，我们评估了来自RBPJ过表达的巨噬细胞的外体(RBPJ+/+Mφ-Exo)在肝癌中的作用。用环状RNA微阵列技术检测φ+/+Mφ-Exo和Thp-1样巨噬细胞(WT M)-Exo的环状RNA(CircRNA)谱。用CCK-8、Transwell和流式细胞仪检测Mφ-exo-CircRNA对肝癌细胞的作用。荧光素酶报告分析、RNA免疫沉淀和皮尔逊相关分析用于确认相互作用。采用裸鼠移植瘤模型，进一步分析Mφ-外环RNA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抑制肝癌细胞增殖和促进细胞凋亡，而hSA_CIRC_0004658基因敲除可促进细胞增殖和迁移，但在体外抑制细胞凋亡，促进肿瘤生长。RBPJ+/+Mφ-exo对肝癌细胞的作用可被hSA_CIRC_0004658基因敲除所逆转。机制研究表明，hSA_CIRC_0004658作为miR-499B-5P的CENA，导致JAM3的表达下调。这些结果表明，RBPJ+/+Mφ分泌的外体CircRNA通过hSA_CIRC_0004658/miR-499b-5p/JAM3途径抑制肿瘤的进展，hSA_CIRC_0004658可能是肝癌诊断的生物标志物和潜在的治疗靶点。
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.
登录
查看更多内容
影响因子：
3.7
作者：
Kakoschky B;Pleli T;Schmithals C;Zeuzem S;Brüne B;Vogl TJ;Korf HW;Weigert A;Piiper A
通讯作者：
Piiper A
影响因子：
3.7
作者：
Linton SS;Abraham T;Liao J;Clawson GA;Butler PJ;Fox T;Kester M;Matters GL
通讯作者：
Matters GL
影响因子：
5.4
作者：
Li, Xudong;Yin, Aiping;Sun, Jiping
通讯作者：
Sun, Jiping
影响因子：
7.6
作者：
Pinter M;Peck-Radosavljevic M
通讯作者：
Peck-Radosavljevic M
影响因子：
--
作者：
Geybels MS;Fang M;Wright JL;Qu X;Bibikova M;Klotzle B;Fan JB;Feng Z;Ostrander EA;Nelson PS;Stanford JL
通讯作者：
Stanford JL