眼葡萄膜黑色素瘤细胞源性外泌体miR-155经巨噬细胞IκBα/NF-κB通路构建肝转移前炎性微环境的作用及机制研究

葡萄膜黑色素瘤（UM）是成人眼内最常见的致盲、致死性恶性肿瘤。UM易发生转移，转移灶90%位于肝脏，但其转移至肝的机制尚不明确。研究表明肿瘤细胞来源的外泌体（TEXs）参与塑造远端靶器官的肿瘤微环境而促进转移。我们前期研究发现UM细胞存在TEXs，可以优先分布于小鼠肝脏，被巨噬细胞摄取后诱发肝内炎症反应，可以增加动物模型中UM肝转移。并经过初步筛选miR-155可能是TEXs中重要的效应分子，靶点预测与验证实验证实肝内巨噬细胞中的IκBα基因为miR-155的靶基因。本研究旨在前期工作的基础上，进一步验证UM-TEXs中的miR-155在诱导肝内转移前炎性微环境的具体作用，并探讨其对IκBα基因的调控。这对解释UM肝转移的机制有重要意义，为寻找预测肿瘤肝转移的液体活检标志物和靶向治疗提供新的方向和靶点。

Uveal melanoma (UM) is the most common blinding and fatal malignancy in the adult eye, which is easy to metastasize. 90% of the UM metastases are located in the liver. However, the mechanism of UM metastasis is still unclear. Studies have shown that tumor cell derived exosomes (TEXs) participate in the construction of tumor microenvironment of distal target organs to promote metastasis. In our previous study, we confirmed the presence of TEXs in UM cells, which can be preferentially distributed in the liver of mice. And then induced inflammatory response after uptake by hepatic macrophages, whicn can promote metastasis of UM to the liver in animal models. MiR-155 was initially screened as an important effector molecule in UM-TEXs. Target prediction and validation assay indicated that IκBα was the target gene of miR-155. In this proposal, we will further verify the role of miR-155 in UM-TEXs for inducing the pre-metastasis inflammatory microenvironment in the liver, and investigate the regulation effect of IκBα. Our study will not only reveal a novel mechanism of UM metastasis to liver, but also provide a new direction and a target for finding liquid biopsy marker and targeted therapy to predict liver metastasis of tumor.