miR-100 maintains phenotype of tumor-associated macrophages by targeting mTOR to promote tumor metastasis via Stat5a/IL-1ra pathway in mouse breast cancer.
miR-100 maintains phenotype of tumor-associated macrophages by targeting mTOR to promote tumor metastasis via Stat5a/IL-1ra pathway in mouse breast cancer.
复制标题
在小鼠乳腺癌中，miR-100 通过靶向 mTOR 维持肿瘤相关巨噬细胞的表型，通过 Stat5a/IL-1ra 通路促进肿瘤转移。
DOI：
10.1038/s41389-018-0106-y
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发表时间：
2018
期刊：
影响因子：
6.2
通讯作者：
Luo Yunping
中科院分区：
文献类型：
--
作者：
Wang Wei;Liu Yan;Guo Jian;He Huiwen;Mi Xue;Chen Chong;Xie Junling;Wang Shengnan;Wu Peng;Cao Fengqi;Bai Lipeng;Si Qin;Xiang Rong;Luo Yunping
肿瘤相关巨噬细胞（Tumor-associated macrophages，TAMs）是肿瘤微环境（tumor microenvironment，TME）中免疫细胞的主要组成部分，通过刺激血管生成、促进肿瘤迁移、抑制抗肿瘤免疫等机制，在肿瘤发生中发挥重要作用。microRNAs（miRNAs）被认为是多种生物过程中的重要调控因子。miRNAs与巨噬细胞功能的关系已被广泛报道，但miRNAs在调节TAMs表型中的作用尚不清楚。在本研究中，我们筛选了TAMs中高表达的microRNA，并首次发现miR-100代表TAMs高表达模式，并通过靶向mTOR信号通路维持TAMs表型。此外，TAM中的miR-100表达水平与IL-1 ra分泌呈正相关，IL-1 ra是一种传统的免疫抑制细胞因子，其被确定通过刺激Hedgehog途径促进肿瘤细胞的干细胞化。机制研究提示mTOR/Stat 5a通路参与了miR-100介导的IL-1 ra转录调控过程。更重要的是，在瘤内注射miR-100的4 T1小鼠乳腺癌模型中，肿瘤转移和侵袭能力显著降低，与顺铂的联合治疗显示出更好的益处。在这项研究中，我们证实，高表达的miR-100维持TAMs的表型，并通过增加IL-1 ra的分泌促进肿瘤转移。在小鼠乳腺癌模型中干扰TAM的miR-100表达可抑制TAM的促肿瘤功能并减少肿瘤转移，提示miR-100可作为乳腺癌微环境重塑的潜在治疗靶点。
Tumor-associated macrophages (TAMs), the main part of immune cells in tumor microenvironment (TME), play a potent role in promoting tumorigenesis through mechanisms such as stimulating angiogenesis, enhancing tumor migration and suppressing antitumor immunity. MicroRNAs (miRNAs) are considered as crucial regulators in multiple biological processes. The relationship between miRNAs and macrophages function has been extensively reported, but the roles that miRNAs play in regulating TAMs phenotype remain unclear. In this study, we screened highly expressed microRNAs in TAMs, and first identified that miR-100 represented a TAMs-high expression pattern and maintained TAMs phenotype by targeting mTOR signaling pathway. Moreover, miR-100 expression level in TAMs was positively related to IL-1ra secretion, a traditional immune-suppressive cytokine, which was determined to promote tumor cells stemness via stimulating Hedgehog pathway. Mechanism study suggested that mTOR/Stat5a pathway was involved in IL-1ra transcriptional regulation process mediated by miR-100. More importantly, tumor metastasis and invasion capacity were significantly decreased in a 4T1 mouse breast cancer model injected intratumorally with miR-100 antagomir, and combination therapy with cisplatin showed much better benefit. In this study, we confirm that highly expressed miR-100 maintains the phenotype of TAMs and promotes tumor metastasis via enhancing IL-1ra secretion. Interfering miR-100 expression of TAMs in mouse breast cancer model could inhibit TAMs pro-tumor function and reduce tumor metastasis, which suggests that miR-100 could serve as a potential therapy target to remodel tumor microenvironment in breast cancer.