Renal cell carcinoma-derived exosomes deliver lncARSR to induce macrophage polarization and promote tumor progression via STAT3 pathway.
Renal cell carcinoma-derived exosomes deliver lncARSR to induce macrophage polarization and promote tumor progression via STAT3 pathway.
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DOI：
10.7150/ijbs.70289
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发表时间：
2022
影响因子：
9.2
通讯作者：
Chen, Wei
中科院分区：
文献类型：
--
作者：
Zhang, Wei;Zheng, Xiaoxiao;Yu, Yisong;Zheng, Li;Lan, Jiahua;Wu, Ying;Liu, Hao;Zhao, An;Huang, Hang;Chen, Wei
肿瘤来源的外泌体通过介导肿瘤微环境中肿瘤细胞和免疫细胞（如巨噬细胞）之间的串扰在调节肿瘤进展中发挥关键作用。巨噬细胞可以采取两种不同的极化状态，并在M1或M2激活表型之间切换，以响应不同的外部刺激。然而，肿瘤来源的外泌体在巨噬细胞表型转换和肿瘤发展中的作用尚未在肾细胞癌（RCC）中阐明。在这里，我们发现高巨噬细胞浸润与RCC患者的预后不良相关，因此我们提出我们的假设，RCC来源的外泌体可能直接影响巨噬细胞极化，从而促进肿瘤进展。构建了基于细胞的体外模型和原位移植体内肿瘤模型，并进行了ELISA、流式细胞术和巨噬细胞功能研究，以研究RCC衍生的外泌体是否以及如何调节巨噬细胞极化和肿瘤生长。结果发现，这些外泌体促进巨噬细胞极化、细胞因子释放、吞噬作用、血管生成和肿瘤发展。进一步的研究显示，在RCC衍生的外泌体中存在大量最近发现的称为lncARSR的lncRNA。lncARSR的过表达在体外诱导巨噬细胞表型和功能的改变，并促进体内肿瘤的生长，而通过siRNA敲低lncARSR破坏外泌体介导的巨噬细胞极化。LncARSR直接与miR-34/miR- 449相互作用以增加RCC细胞中STAT 3表达并介导巨噬细胞极化。RCC衍生的外泌体通过转移lncARSR诱导巨噬细胞极化促进肿瘤的发展，表明RCC衍生的外泌体、lncARSR和STAT 3是治疗RCC的潜在治疗靶点。
Tumor-derived exosomes play a pivotal role in regulating tumor progression by mediating crosstalk between tumor cells and immune cells such as macrophages within the tumor microenvironment. Macrophages can adopt two distinct polarization statuses and switch between M1 or M2 activation phenotypes in response to the different external stimuli. However, the role of tumor derived exosomes in the macrophage phenotypic switch and tumor development have not been elucidated in renal cell carcinoma (RCC). Here we found that high macrophage infiltration was associated with worse prognosis in RCC patients, therefore we propose our hypothesis that RCC derived exosomes might directly influence macrophage polarization and thus promote tumor progression. Both cell-based in vitro models and orthotopic transplantation in vivo tumor models were constructed and ELISA, flow cytometry, and macrophage functional studies were performed to investigate whether and how RCC-derived exosomes regulate macrophage polarization and tumor growth. The results found that these exosomes promote macrophage polarization, cytokine release, phagocytosis, angiogenesis, and tumor development. Further study revealed high amount of a recently discovered lncRNA called lncARSR in RCC-derived exosomes. Overexpression of lncARSR induced phenotypic and functional changes of macrophages in vitro and promoted tumor growth in vivo, while knockdown of lncARSR by siRNA disrupted the exosomes-mediated macrophage polarization. LncARSR interacts directly with miR-34/miR- 449 to increase STAT3 expression and mediate macrophage polarization in RCC cells. Together, RCC-derived exosomes facilitate the development of tumor through inducing macrophage polarization via transferring lncARSR, suggesting that RCC-derived exosomes, lncARSR and STAT3 are the potential therapeutic targets for treatment of RCC.
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影响因子：
19
作者：
Bakir B;Chiarella AM;Pitarresi JR;Rustgi AK
通讯作者：
Rustgi AK
DOI：
10.1186/s13046-021-01870-5
发表时间：
2021-02-23
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Kumar B;Ahmad R;Giannico GA;Zent R;Talmon GA;Harris RC;Clark PE;Lokeshwar V;Dhawan P;Singh AB
通讯作者：
Singh AB
影响因子：
3.2
作者：
Saad AM;Gad MM;Al-Husseini MJ;Ruhban IA;Sonbol MB;Ho TH
通讯作者：
Ho TH
影响因子：
2.5
作者：
Santoni M;Conti A;Piva F;Massari F;Ciccarese C;Burattini L;Cheng L;Lopez-Beltran A;Scarpelli M;Santini D;Tortora G;Cascinu S;Montironi R
通讯作者：
Montironi R
外泌体传输的 lncARSR 通过充当竞争性内源性 RNA 促进肾癌舒尼替尼耐药
影响因子：
50.3
作者：
Qu, Le;Ding, Jin;Wang, Lin-Hui
通讯作者：
Wang, Lin-Hui