去势治疗后肿瘤相关成纤维细胞外泌体 miR-146a-5p 的丢失导致前列腺癌转移。
Loss of exosomal miR-146a-5p from cancer-associated fibroblasts after androgen deprivation therapy contributes to prostate cancer metastasis.
机构信息
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China.
Institute of Urology, Shanghai Jiao Tong University, Shanghai, 200080, China.
出版信息
J Exp Clin Cancer Res. 2020 Dec 14;39(1):282. doi: 10.1186/s13046-020-01761-1.
BACKGROUND
Androgen deprivation therapy (ADT) is the backbone of therapy for advanced prostate cancer (PCa). Despite the good initial response, castration resistance and metastatic progression will inevitably occur. Cancer-associated fibroblasts (CAFs) may be implicated in promoting metastasis of PCa after ADT. Our aim is to investigate the role and mechanism of CAFs-derived exosomes involving in metastasis of PCa after ADT.
METHODS
PCa cells were co-cultured with exosomes derived from 10 nM dihydrotestosterone (DHT)-treated (simulating the high androgen level of prostate cancer microenvironment) or ethanol (ETOH) -treated (simulating the castration level of prostate cancer microenvironment after ADT) CAFs, and their migration and invasion differences under castration condition were examined both in vitro and in vivo. The miRNA profiles of exosomes derived from DHT-treated CAFs and matched ETOH-treated CAFs were analysed via next generation sequencing. The transfer of exosomal miR-146a-5p from CAFs to PCa cells was identified by fluorescent microscopy. The function and direct target gene of exosomal miR-146a-5p in PCa cells were confirmed through Transwell assays, luciferase reporter, and western blot.
RESULTS
Compared with DHT-treated CAFs, exosomes derived from ETOH-treated CAFs dramatically increased migration and invasion of PCa cells under castration condition. MiR-146a-5p level in exosomes from ETOH-treated CAFs was significantly reduced. The loss of miR-146a-5p may strengthen the epithelial-mesenchymal transition (EMT) to accelerate cancer cells metastasis by modulating epidermal growth factor receptor (EGFR)/ERK pathway.
CONCLUSIONS
CAFs-derived exosomal miR-146a-5p confers metastasis in PCa cells under ADT through the EGFR/ERK pathway and it may present a new treatment for PCa.
背景
去势治疗（ADT）是晚期前列腺癌（PCa）治疗的基础。尽管初始反应良好，但不可避免地会发生去势抵抗和转移进展。癌相关成纤维细胞（CAFs）可能参与促进 ADT 后 PCa 的转移。我们的目的是研究 ADT 后 CAFs 衍生的外泌体在 PCa 转移中的作用和机制。
方法
将 PCa 细胞与来自 10 nM 二氢睾酮（DHT）处理（模拟前列腺癌微环境中的高雄激素水平）或乙醇（ETOH）处理（模拟 ADT 后前列腺癌微环境中的去势水平）的 CAFs 衍生的外泌体共培养，并在体外和体内检查它们在去势条件下的迁移和侵袭差异。通过下一代测序分析来自 DHT 处理的 CAFs 和匹配的 ETOH 处理的 CAFs 的外泌体中的 miRNA 图谱。通过荧光显微镜鉴定外泌体 miR-146a-5p 从 CAFs 转移到 PCa 细胞。通过 Transwell 测定、荧光素酶报告和 Western blot 证实外泌体 miR-146a-5p 在 PCa 细胞中的功能和直接靶基因。
结果
与 DHT 处理的 CAFs 相比，来自 ETOH 处理的 CAFs 的外泌体在去势条件下显著增加了 PCa 细胞的迁移和侵袭。来自 ETOH 处理的 CAFs 的外泌体中的 miR-146a-5p 水平显着降低。miR-146a-5p 的丧失可能通过调节表皮生长因子受体（EGFR）/ERK 通路来增强上皮-间充质转化（EMT），从而加速癌细胞转移。
结论
ADT 下 CAFs 衍生的外泌体 miR-146a-5p 通过 EGFR/ERK 通路赋予 PCa 细胞转移能力，这可能为 PCa 提供一种新的治疗方法。
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