Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer.
Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer.
复制标题
肿瘤源性外泌体miR-934诱导巨噬细胞M2极化促进结直肠癌肝转移
DOI：
10.1186/s13045-020-00991-2
复制
发表时间：
2020-11-19
影响因子：
28.5
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
Zhao S;Mi Y;Guan B;Zheng B;Wei P;Gu Y;Zhang Z;Cai S;Xu Y;Li X;He X;Zhong X;Li G;Chen Z;Li D
背景越来越多的证据表明肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）和外来体在转移前小生境的形成中至关重要。然而，肿瘤衍生的外泌体miRNA与TAMs相互作用的分子机制在很大程度上仍然未知的转移前的龛形成和结直肠癌肝转移（CRLM）。MethodsTransmission electron microscopy and differential ultracentraggation被用来验证外泌体的存在。使用体内和体外测定来鉴定外泌体miR-934的作用。应用RNA pull-down分析、双荧光素酶报告基因分析等方法，探讨miR-934调控结直肠癌细胞与M2巨噬细胞间相互作用的机制。结果本研究首次发现miR-934在结直肠癌（CRC）中异常过表达，尤其是在CRLM中，其与CRC患者预后不良的相关性。然后，我们验证了CRC细胞来源的外泌体miR-934通过下调PTEN表达和激活PI 3 K/AKT信号通路诱导M2巨噬细胞极化。此外，我们发现hnRNPA 2B 1介导miR-934包装到CRC细胞的外泌体中，然后将外泌体miR-934转移到巨噬细胞中。有趣的是，极化的M2巨噬细胞可以通过分泌CXCL 13，激活CRC细胞中的CXCL 13/CXCR 5/NFκB/p65/miR-934正反馈环，诱导转移前龛形成，促进CRLM。这些发现揭示了肿瘤和TAM在由影响CRLM的肿瘤源性外泌体介导的转移性微环境中的相互作用。本研究也为继发性肝癌提供了理论依据。
BackgroundMounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown.MethodsTransmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages.ResultsIn the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells.ConclusionsThese findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.
登录
查看更多内容
影响因子：
14.9
作者：
Cook KB;Kazan H;Zuberi K;Morris Q;Hughes TR
通讯作者：
Hughes TR
癌症相关成纤维细胞通过SDF-1/CXCR4轴促进子宫内膜癌的进展
影响因子：
28.5
作者：
Teng F;Tian WY;Wang YM;Zhang YF;Guo F;Zhao J;Gao C;Xue FX
通讯作者：
Xue FX
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
4.4
作者：
Kuroda, Etsushi;Ho, Victor;Krystal, Gerald
通讯作者：
Krystal, Gerald
肿瘤相关巨噬细胞的细胞和分子起源。
DOI：
10.1126/science.1252510
发表时间：
2014-05-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franklin RA;Liao W;Sarkar A;Kim MV;Bivona MR;Liu K;Pamer EG;Li MO
通讯作者：
Li MO