TAMs来源的外泌体通过STAT3参与子宫内膜癌肿瘤浸润及血管形成的机制研究

Endometrial carcinoma (EC) is one of the most common malignancies of female reproductive tract. The infiltration of tumor associated macrophages (TAMs) in the microenvironmet was reported to be negatively related with the prognosis of EC. Our previous work found that TAMs secreted exosomes could induce cell invasion and matrigel tubal formation of EC cells, which participated the regulation of EC progress. Our further research found that, STAT3, which is an important factor in inflammation reaction, was significantly up-regulated in TAMs-associated exosomes. Interestingly, the enriched STAT3 in TAMs-Exosomes could not up-regulated its expression in EC cells, but up-regulated the expression of LncRNA-Lethe, which performs an important role in the interferon-mediated immune reaction. Thus, we speculated that TAMs associated Exosomes could regulate the tumor invasion and angiogenesis of EC through STAT3-mediated regulation of LncRNA-Lethe. In this paper, we will explore the effects of TAMs associated Exosomes on the invasion and angiogenesis of EC, and its putative mechanisms.

子宫内膜癌是常见的女性生殖道恶性肿瘤，微环境中肿瘤相关巨噬细胞(TAMs)浸润与其预后呈负相关。我们前期研究发现TAMs来源的外泌体(TAMs-Exosomes)能够诱导EC细胞浸润及体外微管形成，参与其生物学功能调控；进一步分析发现参与炎症反应的重要细胞转录因子--STAT3在TAMs-Exosomes中富集表达；但是富集表达STAT3的Exosomes并不能上调EC细胞中STAT3表达，而是上调了LncRNA-Lethe表达，后者在干扰素介导的免疫应答中发挥重要作用，因此，我们推测TAMs-Exosomes通过STAT3调控LncRNA-Lethe通路参与EC肿瘤浸润及新生血管形成调控。本研究拟以TAMs-Exosomes为研究对象，探讨TAMs对EC浸润及血管新生的作用调控，并初步探讨其可能的作用机制。

子宫内膜癌是最常见的妇科生殖道恶性肿瘤，晚期及复发性内膜癌患者预后较差，因此了解其发生进展的机制对EC的靶向生物治疗提供理论基础。本研究证实了肿瘤相关巨噬细胞CD68浸润与内膜癌患者肿瘤肌层浸润及血管新生相关；与TAMs共培养可诱导体外EC细胞侵袭及血管拟态形成，促进荷瘤裸鼠肿瘤细胞生长。通过进一步机制分析发现，TAMs来源的外泌体参与这一作用过程，TAMs-Exosomes与内膜癌细胞共培养下可以促进肿瘤细胞侵袭及血管新生；进一步质谱分析发现TAMs-Exosomes富集表达STAT3，而STAT3在内膜癌细胞中富集表达不显著；TAMs-Exosomes可通过上调EC细胞中LncRNA-Lethe参与对内膜癌细胞侵袭及血管拟态形成调控，过表达EC细胞中Lethe可诱导肿瘤细胞侵袭能力增加，抑制细胞中NFkappaB通路相关蛋白表达。最后，我们在新鲜肿瘤组织标本及TCGA数据库中进一步验证了内膜癌组织中Lethe表达及其与STAT3及其下游NFkappaB表达的相关性分析，结果发现STAT3与CD68浸润及NFkappaB表达均呈正相关性，NFkappaB与STAT3表达相关性更强。本研究进一步阐述了外泌体在肿瘤相关巨噬细胞对肿瘤细胞发挥生物学功能中的作用，对于TAMs用于子宫内膜癌预后评估及靶向生物治疗靶点研究提供理论基础。