MicroRNA-494 Is Required for the Accumulation and Functions of Tumor-Expanded Myeloid-Derived Suppressor Cells via Targeting of PTEN
MicroRNA-494 Is Required for the Accumulation and Functions of Tumor-Expanded Myeloid-Derived Suppressor Cells via Targeting of PTEN
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DOI：
10.4049/jimmunol.1103505
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发表时间：
2012-06-01
影响因子：
4.4
通讯作者：
Wang, Qingqing
中科院分区：
文献类型：
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作者：
Liu, Yang;Lai, Lihua;Wang, Qingqing
髓系来源的抑制细胞(MDSCs)能有效抑制抗肿瘤免疫反应，并协调有利于肿瘤血管生成和转移的肿瘤微环境。调控肿瘤扩大的MDSCs的积累和功能的分子网络在很大程度上是未知的。在这项研究中，我们发现microRNA-494(miR-494)是通过靶向磷酸酶和张力蛋白同源蛋白(PTEN)和激活Akt通路来调节MDSCs积累和活性的重要角色。研究发现，转化生长因子-β1是导致MDSCs miR-494表达上调的主要肿瘤衍生因子。MiR-494的表达不仅增强了CXCR4介导的MDSC的趋化作用，而且通过靶向PTEN改变了固有的凋亡/存活信号，从而促进了MDSC在肿瘤组织中的聚集。因此，PTEN的下调导致Akt通路的活性增加，进而上调MMPs以促进肿瘤细胞的侵袭和转移。MiR-494基因敲除可显著逆转4T1小鼠乳腺癌MDSCs活性，抑制肿瘤生长和转移。综上所述，我们的研究结果表明，转化生长因子-β1诱导的mdscs中miR-494的表达在调控肿瘤扩增的mdscs的聚集和功能的分子事件中起着关键作用，可能被确定为癌症治疗的潜在靶点。免疫学杂志，2012,188：5500-5510。
Myeloid-derived suppressor cells (MDSCs) potently suppress the anti-tumor immune responses and also orchestrate the tumor microenvironment that favors tumor angiogenesis and metastasis. The molecular networks regulating the accumulation and functions of tumor-expanded MDSCs are largely unknown. In this study, we identified microRNA-494 (miR-494), whose expression was dramatically induced by tumor-derived factors, as an essential player in regulating the accumulation and activity of MDSCs by targeting of phosphatase and tensin homolog (PTEN) and activation of the Akt pathway. TGF-beta 1 was found to be the main tumor-derived factor responsible for the upregulation of miR-494 in MDSCs. Expression of miR-494 not only enhanced CXCR4-mediated MDSC chemotaxis but also altered the intrinsic apoptotic/survival signal by targeting of PTEN, thus contributing to the accumulation of MDSCs in tumor tissues. Consequently, downregulation of PTEN resulted in increased activity of the Akt pathway and the subsequent upregulation of MMPs for facilitation of tumor cell invasion and metastasis. Knockdown of miR-494 significantly reversed the activity of MDSCs and inhibited the tumor growth and metastasis of 4T1 murine breast cancer in vivo. Collectively, our findings reveal that TGF-beta 1-induced miR-494 expression in MDSCs plays a critical role in the molecular events governing the accumulation and functions of tumor-expanded MDSCs and might be identified as a potential target in cancer therapy. The Journal of Immunology, 2012, 188: 5500-5510.