Intervening in hnRNPA2B1-mediated exosomal transfer of tumor-suppressive miR-184-3p for tumor microenvironment regulation and cancer therapy.
Intervening in hnRNPA2B1-mediated exosomal transfer of tumor-suppressive miR-184-3p for tumor microenvironment regulation and cancer therapy.
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干预hnRNPA2B1介导的肿瘤抑制miR-184-3p胞外转移用于肿瘤微环境调节和肿瘤治疗。
DOI：
10.1186/s12951-023-02190-w
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发表时间：
2023-11-14
影响因子：
10.2
通讯作者：
Hu, Fuqiang
中科院分区：
文献类型：
--
作者：
Zhou, Xueqing;Hong, Yiling;Liu, Yupeng;Wang, Li;Liu, Xuan;Li, Yi;Yuan, Hong;Hu, Fuqiang
尽管是常见的恶性肿瘤，但三阴性乳腺癌（TNBC）的发生和发展的分子机制仍不清楚。肿瘤相关巨噬细胞（TAM）通常极化为促肿瘤表型，并且与TNBC的不良预后相关。外泌体是细胞间通讯的重要介质，可由供体细胞主动分泌以重编程受体细胞。肿瘤细胞源性exosomes在肿瘤细胞增殖和肿瘤抗原重编程中的作用及其分子机制有待进一步研究。我们证明，富含miR-184- 3 p的肿瘤细胞来源的外泌体被巨噬细胞摄取，通过靶向EGR 1抑制JNK信号通路，从而诱导巨噬细胞的M2极化并协同促进肿瘤进展。装载有癌基因c-Myc抑制剂JQ 1的纳米颗粒可以通过减少巨噬细胞对Rac 1相关外泌体的摄取来抑制极化过程。更重要的是，首次发现肿瘤抑制性miR-184- 3 p通过与RNA结合蛋白异质性核核糖核蛋白A2 B1（hnRNPA 2B 1）结合而主动分选到外泌体中，从而通过减轻miR-184- 3 p对Mastermind-like 1（MAML 1）的抑制作用而促进肿瘤细胞增殖和转移。在肿瘤细胞中过表达miR-184- 3 p，同时敲低hnRNPA 2B 1，阻断其通过exosomes的分泌，可有效抑制肿瘤的生长和转移。我们的研究表明，hnRNPA 2B 1介导的肿瘤抑制性miR-184- 3 p从乳腺癌细胞到巨噬细胞的外泌体转移是TNBC进展的重要介质，为TNBC的发病机制和治疗策略提供了新的见解。在线版本包含补充材料，可通过10.1186/s12951-023-02190-w获得。
Despite being a common malignant tumor, the molecular mechanism underlying the initiation and progression of triple-negative breast cancers (TNBCs) remain unclear. Tumor-associated macrophages (TAMs) are often polarized into a pro-tumor phenotype and are associated with a poor prognosis of TNBCs. Exosomes, important mediators of cell-cell communication, can be actively secreted by donor cells to reprogram recipient cells. The functions and molecular mechanisms of tumor cell-derived exosomes in TNBCs progression and TAMs reprogramming urgently need to be further explored. We demonstrated that tumor cell-derived exosomes enriched with miR-184-3p were taken up by macrophages to inhibit JNK signaling pathway by targeting EGR1, thereby inducing M2 polarization of macrophages and synergistically promoting tumor progression. Nanoparticles loaded with oncogene c-Myc inhibitor JQ1 could suppress the polarization process by reducing Rac1-related exosome uptake by macrophage. More importantly, it was found for the first time that tumor-suppressive miR-184-3p was actively sorted into exosomes by binding to RNA-binding protein heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), thus facilitating tumor cell proliferation and metastasis by relieving the inhibitory effect of miR-184-3p on Mastermind-like 1 (MAML1). Overexpressing miR-184-3p in tumor cells and simultaneously knocking down hnRNPA2B1 to block its secretion through exosomes could effectively inhibit tumor growth and metastasis. Our study revealed that hnRNPA2B1-mediated exosomal transfer of tumor-suppressive miR-184-3p from breast cancer cells to macrophages was an important mediator of TNBCs progression, providing new insights into TNBCs pathogenesis and therapeutic strategies. The online version contains supplementary material available at 10.1186/s12951-023-02190-w.
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DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
5.9
作者：
Harborg S;Zachariae R;Olsen J;Johannsen M;Cronin-Fenton D;Bøggild H;Borgquist S
通讯作者：
Borgquist S
影响因子：
64.5
作者：
RIDLEY, AJ;PATERSON, HF;HALL, A
通讯作者：
HALL, A
影响因子：
50.3
作者：
Becker A;Thakur BK;Weiss JM;Kim HS;Peinado H;Lyden D
通讯作者：
Lyden D
影响因子：
9
作者：
Lou C;Xiao M;Cheng S;Lu X;Jia S;Ren Y;Li Z
通讯作者：
Li Z