miR141-CXCL1-CXCR2 Signaling-Induced Treg Recruitment Regulates Metastases and Survival of Non-Small Cell Lung Cancer
miR141-CXCL1-CXCR2 Signaling-Induced Treg Recruitment Regulates Metastases and Survival of Non-Small Cell Lung Cancer
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DOI：
10.1158/1535-7163.mct-14-0448
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发表时间：
2014-12-01
影响因子：
5.7
通讯作者：
Wang, Tingting
中科院分区：
文献类型：
--
作者：
Lv, Mingming;Xu, Yujun;Wang, Tingting
非小细胞肺癌(NSCLC)合并恶性胸腔积液(MPE)患者的中位生存期较短，调节性T细胞(Treg)增多。然而，目前尚不清楚MPE中的某些特定因素是否参与了非小细胞肺癌进展过程中Treg的招募。在这里，我们发现MMPE患者的Treg细胞数量增加，并且与患者的存活率呈负相关(P<；0.001)。MPE中CXCL1水平的升高与Tregs的招募有关(P<；0.01)。此外，miR141调控CXCL1在肺癌细胞中的表达，而荧光素酶试验证实CXCL1是miR141的靶标。趋化实验表明，miR141-CXCL1-CXCR2途径调控Tregs向MPE的迁移。此外，miR141在免疫抑制的小鼠模型中显著抑制肿瘤的生长和转移。这种抑制作用是通过CXCL1-CXCR2途径和Tregs的募集来实现的。我们的研究揭示了microRNA与MPE发生之间的因果联系。在机制上，miR141的表达减少与NSCLC合并MPE患者的生存有关，导致CXCL1的产生增加和Treg的募集，以促进肿瘤的免疫逃逸。(C)2014年AACR。
Patients with non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE) have a short median survival time and increased regulatory T cells (Treg). However, it is unclear whether some specific factors in MPE are involved in Treg recruitment in the progression of NSCLC. Here, we found that Treg population was increased in MPE and inversely correlated with patient survival (P < 0.001). Increased level of CXCL1 in MPE was associated with recruitment of Tregs (P < 0.01). Moreover, miR141 regulated expression of CXCL1 in lung cancer cells, whereas the luciferase test confirmed that CXCL1 is a target of miR141. Chemotaxis assay showed that the miR141-CXCL1-CXCR2 pathway regulates migration of Tregs into MPE. Furthermore, miR141 significantly inhibited tumor growth and metastasis in an immunecompetent mouse model. This suppressive function was mediated by the CXCL1-CXCR2 pathway and recruitment of Tregs. Our study uncovered a causative link between microRNA and development of MPE. Mechanistically, decreased expressions of miR141, associated with the survival of patients with NSCLC with MPE, resulted in the increased production of CXCL1 and recruitment of Tregs to promote immune escape of tumor. (C) 2014 AACR.