NF-κB-regulated exosomal miR-155 promotes the inflammation associated with arsenite carcinogenesis
NF-κB-regulated exosomal miR-155 promotes the inflammation associated with arsenite carcinogenesis
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DOI：
10.1016/j.canlet.2016.11.027
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发表时间：
2017-03-01
期刊：
影响因子：
9.7
通讯作者：
Liu, Qizhan
中科院分区：
文献类型：
--
作者：
Chen, Chao;Luo, Fei;Liu, Qizhan
在癌症微环境中，细胞外通讯允许各种类型的细胞协调和执行生物功能。新出现的证据表明，外泌体作为细胞通讯的介质，参与肿瘤的进展。然而，关于外泌体miRNA调节亚砷酸盐诱导的肝癌中炎症浸润的机制知之甚少。本研究旨在确定从亚砷酸盐转化的人肝上皮（L-02）细胞分泌的miRNA是否转移到正常L-02和THLE-3细胞中，这些细胞在受体细胞中具有功能活性。结果显示，来自亚砷酸盐转化的L-02细胞的外泌体增强正常L-02和THLE-3细胞的miR-155表达和促炎性质。转化细胞通过外泌体将miR-155转移到正常L-02细胞中。siRNA和抑制剂对NF-κ B的抑制降低了来源于转化的L-02细胞的外来体中的miR-155水平，阻断了炎症。亚砷酸盐转化的细胞分泌外泌体以增强炎症，但抑制外泌体的合成不能刺激炎症。miR-155参与外来体介导的肿瘤和正常肝细胞之间的细胞间通讯。此外，砷暴露组大鼠血清中miR-155、IL-6和IL-8均过表达。miR-155与IL-6、IL-8水平呈正相关。此外，外泌体miR-155在砷暴露组血清中表达上调。因此，这些结果表明，来源于转化的L-02细胞的外来体将miR-155转移到周围细胞，这诱导正常肝细胞的促炎活性。这些发现支持了外泌体miRNAs参与环境化学物质诱导的致癌过程中的细胞通讯的概念。(C)2016爱思唯尔爱尔兰有限公司版权所有。
In the cancer microenvironment, extracellular communication allows various types of cells to coordinate and execute biological functions. Emerging evidence indicates that exosomes, as mediators of cell communication, are involved in tumor progression. Little is known, however, about the mechanism by which exosomal miRNAs regulate inflammatory infiltration in arsenite-induced liver cancer. The present research aimed to determine if miRNAs secreted from arsenite-transformed human hepatic epithelial (L-02) cells are transferred into normal L-02 and THLE-3 cells, which are functionally active in the recipient cells. The results show that the exosomes from arsenite-transformed L-02 cells enhance miR-155 expression and the pro-inflammatory properties of normal L-02 and THLE-3 cells. Transformed cells transfer miR-155 into normal L-02 cells via exosomes. The inhibition of NF-kappa B by siRNA and inhibitor, which reduces miR-155 levels in exosomes derived from transformed L-02 cells, blocks inflammation. Arsenite-transformed cells secrete exosomes to enhance inflammation, but the inhibition of the synthesis of exosomes fails to stimulate inflammation. miR-155 is involved in exosome-mediated intercellular communication between neoplastic and normal liver cells. In addition, miR-155, IL-6, and IL-8 were over-expressed in the serum of arsenite exposure group. And there was a positive correlation between miR-155 and IL-6 or IL-8 levels. Further, exosomal miR-155 was up-regulated in the serum of arsenite exposure group. Thus, these results show that exosomes derived from transformed L-02 cells transfer miR-155 to surrounding cells, which induces pro-inflammatory activity of normal liver cells. The findings support the concept that exosomal miRNAs are involved in cell cell communication during carcinogenesis induced by environmental chemicals. (C) 2016 Elsevier Ireland Ltd. All rights reserved.