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.

中文翻译：

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子宫内膜癌细胞通过在缺氧条件下传递外泌体miRNA-21来促进M2样巨噬细胞极化。

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，它与肿瘤分级，淋巴结转移和肿瘤对化疗的耐药性显着相关。但是，EC中的缺氧与免疫微环境之间的关系还不是很清楚。外泌体是从多种细胞类型分泌的小膜囊泡，可通过转运的生物分子介导细胞间的通讯。在这里，我们调查了外泌体是否可以在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细胞在缺氧或常氧条件下培养，以收集外来体。确认后 将缺氧或常氧的KEL细胞衍生的外泌体与单核细胞系THP-1一起培养，以研究KEL细胞的免疫调节功能。结果表明，低氧KEL细胞产生的外泌体总数显着高于常氧条件下。另外，低氧显着刺激了外泌体中miRNA-21表达的增加。共培养后，我们发现外泌体miRNA-21可以水平转移到THP-1细胞中。然后，观察到THP-1细胞中IL-10和CD206的mRNA表达水平显着增强，提示M2极化。为了进一步研究含miRNA-21的外来体的作用，我们将miRNA-21模拟物或抑制剂转染到THP-1细胞中。结果显示，miRNA-21模拟物可促进IL-10和CD206 mRNA表达水平，miRNA-21抑制剂可显着防止因摄入低氧的KEL细胞衍生的外泌体而引起的改变。总之，我们发现处于缺氧状态的子宫内膜癌KEL细胞通过传递外泌体miRNA-21促进单核细胞THP-1细胞转化为M2型极化巨噬细胞，这可能是EC进展中免疫微环境形成的潜在机制。