上皮性卵巢癌细胞来源的细胞外囊泡包裹的 miR-181c-5p 通过 KAT2B/HOXA10 轴促进肿瘤相关巨噬细胞向 M2 极化。
Extracellular vesicle-packaged miR-181c-5p from epithelial ovarian cancer cells promotes M2 polarization of tumor-associated macrophages via the KAT2B/HOXA10 axis.
机构信息
Department of Obstetrics and Gynecology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, P. R. China.
Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, P. R. China.
出版信息
J Gene Med. 2022 Oct;24(10):e3446. doi: 10.1002/jgm.3446. Epub 2022 Sep 19.
OBJECTIVES
The molecular mechanistic actions of tumor-derived extracellular vesicles (EVs) in modulating macrophage polarization in the tumor microenvironment of epithelial ovarian cancer (EOC) is largely unknown. The study was performed to clarify the effect and downstream mechanism of microRNA-181c-5p (miR-181c-5p)-containing EVs from EOC cells in the M2 polarization of tumor-associated macrophages (TAMs).
METHODS
EVs were isolated from normoxic and hypoxic human EOC cells SKOV3. Human mononuclear cell THP-1 was induced by phorbol-12-myristate-13-acetate to differentiate into TAMs. The targeting relationship between miR-181c-5p and KAT2B was verified by dual luciferase reporter gene assay. The interaction between KAT2B and HOXA10 was detected by immunofluorescence, Co-IP and ChIP assays. EdU staining, the scratch test and Transwell assay were used to assess the resultant cell proliferation, migration and invasion. The mouse xenograft model and the pulmonary metastasis model were developed through intraperitoneal injection of SKOV3 cells and tail vein injection of THP-1 cells, respectively.
RESULTS
Hypoxic SKOV3 cell-derived EVs could be internalized by TAMs. SKOV3 cell-derived EVs induced by hypoxia (H-EVs) promoted M2 polarization of TAMs and facilitated the proliferation, migration and invasion of SKOV3 cells. miR-181c-5p was highly expressed in H-EVs and promoted the M2 polarization of TAMs. Further, miR-181c-5p targeted KAT2B, upregulated HOXA10 and activated the JAK1/STAT3 pathway, thereby promoting the M2 polarization of TAMs. In both mouse models, H-EV-derived miR-181c-5p promoted growth and metastasis of EOC cells.
CONCLUSION
The miR-181c-5p-containing EVs from hypoxic EOC cells may upregulate HOXA10 by targeting KAT2B and activate the JAK1/STAT3 pathway to promote the M2 polarization of TAMs, ultimately promoting growth and metastasis of EOC cells in vitro and in vivo.
目的
肿瘤来源的细胞外囊泡（EVs）在调节上皮性卵巢癌（EOC）肿瘤微环境中巨噬细胞极化的分子机制尚不清楚。本研究旨在阐明 EOC 细胞来源的含 microRNA-181c-5p（miR-181c-5p）的 EVs 在肿瘤相关巨噬细胞（TAMs）M2 极化中的作用及其下游机制。
方法
从常氧和低氧人 EOC 细胞 SKOV3 中分离 EVs。人单核细胞 THP-1 用佛波醇 12-肉豆蔻酸 13-乙酸诱导分化为 TAMs。通过双荧光素酶报告基因检测验证 miR-181c-5p 与 KAT2B 的靶向关系。通过免疫荧光、Co-IP 和 ChIP 检测检测 KAT2B 与 HOXA10 之间的相互作用。EdU 染色、划痕试验和 Transwell 试验用于评估细胞增殖、迁移和侵袭的结果。通过腹腔注射 SKOV3 细胞和尾静脉注射 THP-1 细胞分别建立小鼠异种移植模型和肺转移模型。
结果
低氧 SKOV3 细胞衍生的 EVs 可被 TAMs 内化。缺氧诱导的 SKOV3 细胞衍生的 EVs（H-EVs）促进了 TAMs 的 M2 极化，并促进了 SKOV3 细胞的增殖、迁移和侵袭。miR-181c-5p 在 H-EVs 中高表达，并促进了 TAMs 的 M2 极化。此外，miR-181c-5p 靶向 KAT2B，上调 HOXA10 并激活 JAK1/STAT3 通路，从而促进 TAMs 的 M2 极化。在两种小鼠模型中，H-EV 衍生的 miR-181c-5p 促进了 EOC 细胞的生长和转移。
结论
低氧 EOC 细胞来源的含 miR-181c-5p 的 EVs 可能通过靶向 KAT2B 上调 HOXA10 并激活 JAK1/STAT3 通路，促进 TAMs 的 M2 极化，最终促进体内外 EOC 细胞的生长和转移。
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