Endometrial Cancer Cells Promote M2-Like Macrophage Polarization by Delivering Exosomal miRNA-21 under Hypoxia Condition.
Endometrial Cancer Cells Promote M2-Like Macrophage Polarization by Delivering Exosomal miRNA-21 under Hypoxia Condition.
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子宫内膜癌细胞在缺氧条件下通过传递外泌体 miRNA-21 促进 M2 样巨噬细胞极化
DOI：
10.1155/2020/9731049
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发表时间：
2020
影响因子：
4.1
通讯作者：
Yuan C
中科院分区：
文献类型：
--
作者：
Xiao L;He Y;Peng F;Yang J;Yuan C
越来越多的证据表明，缺氧是子宫内膜癌(EC)的一种侵袭性特征，它与肿瘤的分级、淋巴结转移和肿瘤对化疗的抵抗力密切相关。然而，低氧与EC免疫微环境的关系尚不十分清楚。胞外体是由多种类型的细胞分泌的小的膜泡，通过运输的生物分子来调节细胞间的通讯。在这里，我们研究了外切体是否可以在EC细胞和巨噬细胞之间的细胞间通讯中发挥免疫调节作用。EC KEL细胞在低氧或常氧条件下培养，收集外切体。经鉴定后，将低氧或常氧KEL细胞来源的外切体与单核细胞系THP-1共同培养，研究KEL细胞的免疫调节功能。结果表明，KEL细胞在低氧条件下产生的外切体总数显著高于常氧条件下产生的外切体总数。此外，低氧显著刺激外体miRNA-21的表达增加。共培养后，我们发现外体miRNA-21可以水平转移到THP-1细胞中。THP-1细胞中IL-10和CD206的mRNA表达水平显著升高，提示M2极化。为了进一步研究含有miRNA-21外切体的作用，我们将miRNA-21模拟物或抑制剂导入THP-1细胞。结果表明，miRNA-21模拟物可促进IL-10和CD206的mRNA表达水平，而miRNA-21抑制剂可显著抑制因摄入低氧Kel细胞来源的外切体而引起的改变。综上所述，我们发现低氧状态下子宫内膜癌KEL细胞通过递送外体miRNA-21促进单核细胞THP-1向M2样极化巨噬细胞转化，这可能是EC进展过程中免疫微环境形成的一个潜在机制。
Increasing evidence has demonstrated that hypoxia was an aggressive feature in endometrial cancer (EC), which is significantly associated with the tumor grade, lymph node metastasis, and tumor resistance to chemotherapy. However, the relationship between hypoxia and the immune microenvironment in EC is not very clear. Exosomes are small membrane vesicles secreted from a variety of cell types which mediate cell-to-cell communication through transported biomolecules. Here, we investigated whether exosomes can play an immunomodulatory role in intercellular communication between EC cells and macrophages. EC KEL cells were cultured under hypoxia or normoxic condition to collect exosomes. After identification, the exosomes derived from hypoxic or normoxic KEL cells were cultured with the monocyte cell line THP-1 to study the immunoregulation function of KEL cells. The results showed that the total number of exosomes produced by hypoxic KEL cells was significantly higher than that in normoxic condition. In addition, hypoxia markedly stimulated the increase in miRNA-21 expression in the exosomes. After coculture, we found that exosomal miRNA-21 could be horizontally transferred into THP-1 cells. And then, the notably enhanced mRNA expression levels of IL-10 and CD206 in THP-1 cells were observed, suggestive of M2 polarization. To further study the effect of miRNA-21-containing exosomes, we transfected miRNA-21 mimics or inhibitor into THP-1 cells. The results showed that miRNA-21 mimics promoted IL-10 and CD206 mRNA expression levels, and the miRNA-21 inhibitor significantly prevented the alteration induced by intake of hypoxic KEL cell-derived exosomes. In summary, we found that endometrial cancer KEL cells in hypoxic condition promoted monocyte THP-1 cell transformation to M2-like polarization macrophages through delivering exosomal miRNA-21, which may be a potential mechanism of the formation of the immune microenvironment in EC progression.
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