miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization (Retracted article. See vol. 16, 2023)
miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization (Retracted article. See vol. 16, 2023)
复制标题
miR-195-5p/NOTCH2介导的EMT调节结直肠癌中IL-4的分泌以影响M2样TAM极化
DOI：
10.1186/s13045-019-0708-7
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发表时间：
2019-02-26
影响因子：
28.5
通讯作者：
Xiong, Bin
中科院分区：
文献类型：
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作者：
Lin, Xiaobin;Wang, Shuyi;Xiong, Bin
肿瘤微环境（TME）是一个由肿瘤细胞、肿瘤相关巨噬细胞（TAMs）、间质细胞和非细胞成分组成的复杂环境。上皮-间质转化（EMT）是肿瘤发生和转移的重要因素，参与了TAM与肿瘤细胞的相互作用。然而，EMT的潜在机制以及EMT编程的肿瘤细胞如何影响M2样TAMs仍需进一步探索。使用功能测定，包括EdU、克隆形成、伤口愈合和transwell测定，来确定miR-195- 5 p在人CRC进展中的抗癌作用。此外，使用RNA免疫沉淀、RNA衰变和双荧光素酶报告基因测定来确定miR-195-p CRC进展的机制。然后应用共培养、迁移和ELISA测定来确定miR-195- 5 p在巨噬细胞募集和交替极化中的作用。使用异种移植小鼠模型来确定miR-195- 5 p在CRC致瘤性和TAM polarization in vivo.ResultsAn integrated analysis证实miR-195- 5 p在CRC组织中显著下调，并且如TCGA-COAD数据集所揭示的，具有低水平miR-195- 5 p的患者的总生存期显著缩短。miR-195- 5 p在结肠癌细胞中的改变导致增殖、迁移、侵袭和EMT的明显变化。在机制上，miR-195- 5 p通过直接结合Notch 2 mRNA的3-UTR以转录后方式调节NOTCH 2表达。结论miR-195- 5 p/NOTCH 2可能在调控NOTCH 2介导的肿瘤细胞EMT中发挥重要作用，从而影响IL-4相关的M2样TAM极化。
BackgroundTumor microenvironment (TME) is a complex environment containing tumor cells, tumor-associated macrophages (TAMs), interstitial cells, and non-cellular components. Epithelial-mesenchymal transition (EMT), as a major actor in cancer tumorigenicity and metastasis, was involved in the interaction between TAMs and tumor cells. However, the potential mechanisms of EMT and how EMT-programmed tumor cells affect M2-like TAMs still need further exploration.MethodsAn integrated analysis of nine CRC miRNA expression datasets was performed. Functional assays, including the EdU, clone formation, wound healing, and transwell assays, were used to determine the anticancer role of miR-195-5p in human CRC progression. Furthermore, RNA immunoprecipitation, RNA decay, and dual-luciferase reporter assays were used to determine the mechanism of miR-195-p CRC progression. Then co-culture, migration, and ELISA assays were applied to determine the role of miR-195-5p in macrophage recruitment and alternative polarization. Xenograft mouse models were used to determine the role of miR-195-5p in CRC tumorigenicity and TAM polarization in vivo.ResultsAn integrated analysis confirmed that miR-195-5p was significantly downregulated in CRC tissues, and patients with a low level of miR-195-5p had significantly shortened overall survival as revealed by the TCGA-COAD dataset. Altered miR-195-5p in colon cancer cells led to distinct changes of proliferation, migration, invasion, and EMT. Mechanistically, miR-195-5p regulated NOTCH2 expression in a post-transcriptional manner by directly binding to 3-UTR of the Notch2 mRNA. Subsequently, miR-195-5p/NOTCH2 suppressed GATA3-mediated IL-4 secretion in CRC cells and ultimately inhibited M2-like TAM polarization.ConclusionsmiR-195-5p may play a vital role in regulating NOTCH2-mediated tumor cell EMT, thereby affecting IL-4-related M2-like TAM polarization in CRC.