Hypoxic Lung-Cancer-Derived Extracellular Vesicle MicroRNA-103a Increases the Oncogenic Effects of Macrophages by Targeting PTEN.
Hypoxic Lung-Cancer-Derived Extracellular Vesicle MicroRNA-103a Increases the Oncogenic Effects of Macrophages by Targeting PTEN.
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DOI：
10.1016/j.ymthe.2017.11.016
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发表时间：
2018-02-07
期刊：
影响因子：
--
通讯作者：
Kuo PL
中科院分区：
文献类型：
--
作者：
Hsu YL;Hung JY;Chang WA;Jian SF;Lin YS;Pan YC;Wu CY;Kuo PL
缺氧是癌症中最常见的特征，与免疫抑制小生境的建立有关。最近的研究表明，细胞外囊泡（EV）介导的肿瘤-间质相互作用被认为在调节各种细胞生物学功能中发挥关键作用，并在受体细胞中产生表型后果。然而，在癌症进展过程中EV和缺氧之间关系的潜在机制在很大程度上仍然未知。在这项研究中，我们发现来自低氧肺癌的EV通过miR-103 a转移增加了M2型极化。由低氧癌细胞来源的EV miR-103 a引起的PTEN水平降低增加了AKT和STAT 3的活化以及几种免疫抑制因子和促血管生成因子的表达。相比之下，通过miRNA抑制剂抑制miR-103 a有效地降低了低氧癌症介导的M2型极化，改善了肿瘤浸润巨噬细胞的细胞因子前生命。巨噬细胞接受癌细胞来源的EV miR-103 a反馈，以进一步增强癌症进展和肿瘤血管生成。最后，肺癌患者的循环EV miR-103 a水平较高，并与M2极化密切相关。总之，我们的研究结果描绘了一种新的机制，肺癌细胞通过EV诱导免疫抑制和促肿瘤巨噬细胞，并激发进一步研究EV抑制或PTEN恢复免疫治疗的临床应用。细胞外囊泡（EV）miR-103可以从缺氧癌细胞转移到巨噬细胞，导致通过下调miR-103 a的直接靶点PTEN而增强M2极化。EV miR-103 a增加巨噬细胞对癌症进展和血管生成的刺激作用。
Hypoxia, the most commonly observed characteristic in cancers, is implicated in the establishment of an immunosuppressive niche. Recent studies have indicated that extracellular vesicle (EV)-mediated cancer-stroma interactions are considered to play a critical role in the regulation of various cellular biological functions, with phenotypic consequences in recipient cells. However, the mechanisms underlying the relationship between EVs and hypoxia during cancer progression remain largely unknown. In this study, we found that EVs derived from hypoxic lung cancers increased M2-type polarization by miR-103a transfer. Decreased PTEN levels caused by hypoxic cancer-cell-derived EV miR-103a increased activation of AKT and STAT3 as well as expression of several immunosuppressive and pro-angiogeneic factors. In contrast, inhibition of miR-103a by an miRNA inhibitor effectively decreased hypoxic cancer-mediated M2-type polarization, improving the cytokine prolife of tumor infiltration macrophages. Macrophages received cancer-cell-derived EV miR-103a feedback to further enhance cancer progression and tumor angiogenesis. Finally, circulating EV miR-103a levels were higher in patients with lung cancer and closely associated with the M2 polarization. In conclusion, our results delineate a novel mechanism by which lung cancer cells induce immunosuppressive and pro-tumoral macrophages through EVs and inspire further research into the clinical application of EV inhibition or PTEN restoration for immunotherapy. Extracellular vesicle (EV) miR-103 can be transferred from hypoxic cancer cells to macrophages, resulting in the enhancement of M2 polarization by the downregulation of miR-103a’s direct target PTEN. EV miR-103a increases the stimulatory effects of macrophages on cancer progression and angiogenesis.
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影响因子：
3.9
作者：
Akers, Johnny C.;Ramakrishnan, Valya;Kim, Ryan;Phillips, Shirley;Kaimal, Vivek;Mao, Ying;Hua, Wei;Yang, Isaac;Fu, Chia-Chun;Nolan, John;Nakano, Ichiro;Yang, Yuanfan;Beaulieu, Martin;Carter, Bob S.;Chen, Clark C.
通讯作者：
Chen, Clark C.
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影响因子：
50.3
作者：
Qu, Le;Ding, Jin;Wang, Lin-Hui
通讯作者：
Wang, Lin-Hui
影响因子：
32.4
作者：
Noy, Roy;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.
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
间充质样癌细胞和巨噬细胞之间的正反馈回路对于乳腺癌转移至关重要。
影响因子：
50.3
作者：
Su, Shicheng;Liu, Qiang;Song, Erwei
通讯作者：
Song, Erwei