BMAL1 induces colorectal cancer metastasis by stimulating exosome secretion
BMAL1 induces colorectal cancer metastasis by stimulating exosome secretion
复制标题
BMAL1通过刺激外泌体分泌诱导结直肠癌转移
DOI：
10.1007/s11033-021-06883-z
复制
发表时间：
2021-11-02
影响因子：
2.8
通讯作者：
Lu, Chao
中科院分区：
文献类型：
--
作者：
Dong, Pengjuan;Wang, Yaping;Lu, Chao
为了适应外部环境的日常变化，生物已经形成了周期约为24小时的昼夜节律系统。许多研究报道昼夜节律和外泌体在肿瘤的发生和转移中都起着重要作用。然而，生物钟基因是否可以通过调节外泌体来影响肿瘤的进展仍不清楚。方法和结果在本研究中，我们从人结直肠癌（CRC）细胞（包括SW480、SW620和HCT116细胞）的上清液中分离出外泌体，并通过透射电镜、纳米颗粒跟踪分析和Western blot分析对外泌体进行了表征。然后，我们发现来自SW480、SW620和HCT116细胞的外泌体可以促进HCT116和人脐静脉内皮细胞的迁移。当我们增加核心昼夜节律蛋白BMAL1的表达时，SW620细胞衍生的外泌体显示出增强的刺激作用。相比之下，当我们敲低BMAL1的表达时，来自SW480和HCT116细胞的外泌体的刺激作用减弱。此外，我们发现BMAL1促进HCT116和SW620细胞释放外泌体。此外，通过荧光素酶测定，我们证实BMAL1转录调节Rab27a的表达，Rab27a是外泌体分泌的关键分子。结论sour数据揭示了BMAL1通过刺激外泌体分泌诱导结直肠癌转移的新机制。这一发现可能有助于进一步阐明昼夜节律在结直肠癌进展中的作用。图形抽象
BackgroundTo adapt to daily changes in the external environment, organisms have developed circadian rhythm systems with a period of approximately 24 h. Many studies have reported that both circadian rhythms and exosomes play important roles in the development and metastasis of tumors. However, whether circadian clock genes can affect the progression of tumors by regulating exosomes remains unclear.Methods and resultsIn this study, we isolated exosomes from the supernatant of human colorectal cancer (CRC) cells, including SW480, SW620, and HCT116 cells, by differential centrifugation and characterized exosomes by transmission electron microscopy, nanoparticle tracking analysis, and Western blot analysis. Then, we found that exosomes derived from SW480, SW620 and HCT116 cells could promote the migration of HCT116 and human umbilical vein endothelial cells. Exosomes derived from SW620 cells showed increased stimulating effects when we increased the expression of BMAL1, a core circadian protein. In contrast, exosomes derived from SW480 and HCT116 cells showed decreased stimulating effects when we knocked down the expression of BMAL1. Furthermore, we discovered that BMAL1 promotes the release of exosomes by HCT116 and SW620 cells. In addition, by luciferase assay, we confirmed that BMAL1 transcriptionally regulates the expression of Rab27a, a key molecule related to the secretion of exosomes.ConclusionsOur data reveal a new mechanism by which BMAL1 induces CRC metastasis by stimulating exosome secretion. This finding may help further clarify the role of circadian rhythm in the progression of CRC.Graphic abstract