Tumor-derived exosomal microRNA-106b-5p activates EMT-cancer cell and M2-subtype TAM interaction to facilitate CRC metastasis
Tumor-derived exosomal microRNA-106b-5p activates EMT-cancer cell and M2-subtype TAM interaction to facilitate CRC metastasis
复制标题
肿瘤源性外泌体 microRNA-106b-5p 激活 EMT-癌细胞和 M2 亚型 TAM 相互作用以促进 CRC 转移
DOI：
10.1016/j.ymthe.2021.02.006
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发表时间：
2021-06-02
影响因子：
12.4
通讯作者：
Xiong, Bin
中科院分区：
文献类型：
--
作者：
Yang, Chaogang;Dou, Rongzhang;Xiong, Bin
上皮-间充质转化(EMT)被认为参与了肿瘤细胞和肿瘤相关巨噬细胞(TAMs)之间的相互作用。胞外体被认为是协调细胞间通讯的重要媒介。然而，EMT-结直肠癌(CRC)细胞促进TAM M2极化的潜在机制仍然知之甚少。在本研究中，我们发现EMT-CRC细胞通过将外切小体直接转移到巨噬细胞来促进巨噬细胞的M2样极化，导致巨噬细胞内microRNA-106b-5p(miR-106b)水平显著增加。在机制上，miR-106b水平的增加通过在转录后水平直接抑制程序性细胞死亡4(PDCD4)，激活了磷脂酰肌醇3-激酶(PI3K)γ/AKT/哺乳动物雷帕霉素靶(MTOR)信号通路，导致巨噬细胞M2极化。激活的M2巨噬细胞以正反馈方式促进EMT介导的CRC细胞的迁移、侵袭和转移。临床上，miR106b在结直肠癌组织中显著升高，并与结直肠癌组织中PDCD4水平呈负相关，血浆中外体miR-106b的高表达与结直肠癌的恶性进展密切相关。综上所述，我们的结果表明，来源于EMT-CRC细胞的外体miR-106b在诱导M2巨噬细胞极化的细胞间通讯中具有重要作用，阐明了CRC进展的新机制，并为预防CRC转移提供了潜在的靶点。
Epithelial-mesenchymal transition (EMT) is reported to involve in the crosstalk between tumor cells and tumor-associated macrophages (TAMs). Exosomes are considered as important mediators of orchestrating intercellular communication. However, the underlying mechanisms by which EMT-colorectal cancer (CRC) cells promote the M2 polarization of TAMs remain less understood. In this study, we found that EMT-CRC cells promoted the M2-like polarization of macrophages by directly transferring exosomes to macrophages, leading to a significant increase of the microRNA-106b-5p (miR-106b) level in macrophages. Mechanically, an increased level of miR-106b activated the phosphatidylinositol 3-kinase (PI3K) gamma/AKT/mammalian target of rapamycin (mTOR) signaling cascade by directly suppressing programmed cell death 4 (PDCD4) in a post-transcription level, contributing to the M2 polarization of macrophages. Activated M2 macrophages, in a positive-feedback manner, promote EMT-mediated migration, invasion, and metastasis of CRC cells. Clinically, miR106b was significantly elevated in CRC tissues and negatively correlated with the levels of PDCD4 in CRC specimens, and high expression of exosomal miR-106b in plasma was significantly associated with the malignant progression of CRC. Taken together, our results indicate that exosomal miR-106b derived from EMT-CRC cells has an important role in intercellular communication for inducing M2 macrophage polarization, illuminating a novel mechanism underlying CRC progression and offering potential targets for prevention of CRC metastasis.