miR-146a is directly regulated by STAT3 in human hepatocellular carcinoma cells and involved in anti-tumor immune suppression
miR-146a is directly regulated by STAT3 in human hepatocellular carcinoma cells and involved in anti-tumor immune suppression
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miR-146a在人肝癌细胞中受STAT3直接调控并参与抗肿瘤免疫抑制
DOI：
10.4161/15384101.2014.977112
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发表时间：
2015-01-15
期刊：
影响因子：
4.3
通讯作者：
Tian, Zhigang
中科院分区：
文献类型：
--
作者：
Sun, Xiaoxia;Zhang, Jian;Tian, Zhigang
MicroRNAs （miRNAs）在肿瘤发生中起着重要作用，但它们在肿瘤诱导的免疫抑制中的作用在很大程度上是未知的。STAT3信号是肿瘤微环境中介导免疫抑制的关键通路，负责几种重要mirna的转录。在这项研究中，我们观察到miR-146a，一个已知的重要的免疫反应调节因子，在肝细胞癌（HCC）细胞中通过阻断激活的STAT3而下调。此外，在HCC细胞中抑制miR-146a不仅改变了STAT3激活相关的细胞因子谱，还在体外逆转了HCC诱导的NK细胞功能障碍，并在体内提高了淋巴细胞的抗肿瘤作用。重要的是，ChIP和荧光素酶报告基因检测证实STAT3直接结合到miR-146a启动子并诱导miR-146a表达。这些发现表明，在HCC细胞中，miR-146a的表达受到STAT3异常激活的调控，对抗肿瘤免疫应答产生负面影响，导致TGF-β、IL-17、VEGF等细胞因子上调，I型IFN下调，形成免疫抑制微环境。这一对肿瘤诱导免疫抑制机制的进一步了解凸显了miR-146a作为HCC新的免疫治疗靶点的潜在应用。
MicroRNAs (miRNAs) play an important role in tumorigenesis, but their role in tumor-induced immune suppression is largely unknown. STAT3 signaling, a key pathway mediating immune suppression in the tumor microenvironment, is responsible for the transcription of several important miRNAs. In this study, we observed that miR-146a, a known important regulator of immune responses, was downregulated by blocking activated STAT3 in hepatocellular carcinoma (HCC) cells. Furthermore, miR-146a inhibition in HCC cells not only altered the STAT3 activation–associated cytokine profile but also reversed HCC-induced NK cell dysfunction in vitro and improved the anti-tumor effect of lymphocytes in vivo. Importantly, ChIP and luciferase reporter assays confirmed that STAT3 directly bound to the miR-146a promoter and induced miR-146a expression. These findings indicated that miR-146a expression was regulated by aberrantly activated STAT3 in HCC cells and exerted negative effects on anti-tumor immune response, which resulted in the upregulation of cytokines such as TGF-β, IL-17, VEGF and downregulation of type I IFN to create an immunosuppressive microenvironment. This further insight into understanding the mechanism responsible for tumor-induced immune suppression highlights the potential application of miR-146a as a novel immunotherapeutic target for HCC.