TWEAK调控TAM源性外泌体分选miRNA逆转TAM促卵巢癌转移效应的机制研究

Epithelial ovarian cancer (EOC) is the leading cause of death among patients diagnosed with gynecological malignancies worldwide. Tumor metastasis and lack of efficient therapy are known to be the major factors affecting EOC patient survival. Tumor associated macrophages (TAM) are the major component of the tumor microenvironment and has increasingly been recognized as a contributor to tumor progression and metastasis. Thus, reversal of macrophages compromise is the key point to improve tumor microenvironment, serving as attractive targets for therapeutic intervention. In our previous studies, TWEAK-stimulated macrophages could inhibit metastasis of epithelial ovarian cancer via exosomal shuttling of tumor associated microRNA. In pre-experiments, we verified that TWEAK lead to down-regulated Dicer expression in TAM and Dicer regulate sorting of miRNAs into exosomes derived from TAM. Therefore, the study will investigate into the underlying mechanism of TWEAK regulating the expression of Dicer and the mechanism of Dicer controlling the sorting of miRNAs into exosomes in TAMs. We aim to elucidate the mechanism underlying the regulatory effect of TWEAK on EOC metastasis through sorting of miRNAs into exosomes derived from TAMs, and thus provide reliable evidence for the possible application of TWEAK in EOC treatment

上皮性卵巢癌（EOC）死亡率居妇科恶性肿瘤首位，盆腹腔广泛转移及缺乏有效抑制EOC转移的治疗手段是造成其预后差的主要原因。肿瘤相关巨噬细胞（TAM）是卵巢癌微环境的主要组成成分，逆转其促癌转移效应是调控EOC微环境的重要环节，有望突破EOC治疗瓶颈。我们前期首次报道TWEAK可逆转TAM的促癌转移效应，且TAM源性外泌体转运癌转移相关miRNA至EOC是其重要机制。预实验发现TWEAK可抑制TAM中Dicer表达，而Dicer可调节TAM源性外泌体中癌转移相关miRNA的表达。因此，本项目将研究“TWEAK通过何种途径调节TAM中Dicer的表达”，“TAM中Dicer如何调控TAM源性外泌体分选miRNA进而逆转TAM促EOC转移效应”，以期阐明TWEAK通过调控TAM源性外泌体分选miRNA来影响肿瘤微环境，进而逆转TAM促卵巢癌转移效应的机制，为卵巢癌临床治疗提供新的方法和理论依据。

Erastin是一种能有诱导铁死亡的小分子物质，大量研究表明，Erastin诱导的铁死亡在多种癌症中表现出抗肿瘤作用，如卵巢癌。然而，大多数卵巢癌细胞对Erastin诱导的铁死亡表现出相对耐药。M2型肿瘤相关巨噬细胞（TAMs)对卵巢癌肿瘤微环境（TME）有重要影响，对卵巢癌治疗产生的影响值得关注。Erastin对铁死亡耐药的卵巢癌细胞的免疫调节作用仍尚待探究。本项目发现，低浓度的Erastin极大促进了铁死亡耐药卵巢癌细胞通过STAT3介导的巨噬细胞M2极化促进肿瘤侵袭的迁移。体外试验结果表明，Erastin处理极大增加了铁死亡耐药卵巢癌细胞的转移、大大增加了M2巨噬细胞的比例。此外Erastin促进巨噬细胞表达IL-8，IL-8抑制剂能逆转Erastin对于铁死亡耐药卵巢癌的刺激作用。本研究揭示了Erastin促瘤新机制，STAT3/IL-8轴将有望成为治疗铁死亡耐药卵巢癌的潜在靶点。