MiR-21 controls in situ expansion of CCR6+ regulatory T cells through PTEN/AKT pathway in breast cancer
MiR-21 controls in situ expansion of CCR6+ regulatory T cells through PTEN/AKT pathway in breast cancer
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MiR-21 通过 PTEN/AKT 通路控制乳腺癌中 CCR6( ) 调节性 T 细胞的原位扩增
DOI：
10.1038/icb.2015.37
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发表时间：
2015-09-01
影响因子：
4
通讯作者：
Xu, Lin
中科院分区：
文献类型：
--
作者：
Hu, Yan;Wang, Chunhong;Xu, Lin
我们最近的证据表明，CCR 6（+）Foxp 3（+）调节性T细胞（TCR 4）的预先扩增对于其在肿瘤组织中的优势富集是重要的，这与乳腺癌患者的不良预后密切相关。然而，CCR 6（+）TcR在原位扩增的潜在调控机制仍然很大程度上未知。在这项研究中，我们报道了miR-21在小鼠乳腺癌模型的肿瘤组织中的CCR 6（+）TcR中高度表达。miR-21的沉默可显著抑制CCR 6（+）TcB细胞的体外增殖。连续细胞转移实验进一步表明，沉默miR-21可改变CCR 6（+）T细胞在肿瘤块中的富集，并赋予CD 8（+）T细胞有效的抗肿瘤作用。机制证据表明，miR-21的沉默增强了其靶向磷酸酶和张力蛋白同源物在染色体10上缺失（PTEN）的表达，随后改变了Akt通路的激活，这最终导致CCR 6（+）TcR的增殖活性降低。最后，我们进一步揭示了miR-21在临床乳腺癌患者中也在CCR 6（+）T细胞上高表达。因此，miR-21可以作为一个微调器在调节PTEN/Akt通路转导中CCR 6（+）TcR在肿瘤部位的扩增，并提供了一个新的见解发展的治疗策略，通过调节不同的TcR亚群，通过靶向特定的miRNA促进T细胞免疫。
Our recent evidence showed that prior expansion of CCR6(+) Foxp3(+) regulatory T cells (Tregs) was important for their dominant enrichment in tumor tissue, which was closely related to poor prognosis of breast cancer patients. However, the underlying regulation mechanism of expansion of CCR6(+) Tregs in situ remains largely unknown. In this study, we reported that miR-21 was highly expressed in CCR6(+) Tregs in tumor tissues from a murine breast cancer model. And silencing of miR-21 could significantly reduce the proliferation of CCR6(+) Tregs in vitro. Adoptive cell-transfer assay further showed that silencing of miR-21 could alter the enrichment of CCR6(+) Tregs in the tumor mass and endow effectively antitumor effect of CD8(+) T cells using a murine breast cancer model. Mechanistic evidence showed that silencing of miR-21 enhanced the expression of its target phosphatase and tensin homolog deleted on chromosome ten (PTEN) and subsequently altered the activation of Akt pathway, which was ultimately responsible for reduced proliferation activity of CCR6(+) Tregs. Finally, we further revealed that miR-21 was also highly expressed on CCR6(+) Tregs in clinical breast cancer patients. Therefore, miR-21 can act as a fine tuner in the regulation of PTEN/Akt pathway transduction in the expansion of CCR6(+) Tregs in tumor sites and provided a novel insight into the development of therapeutic strategies for promoting T-cell immunity by regulating distinct subset of Tregs through targeting specific miRNAs.