BMAL1 induces colorectal cancer metastasis by stimulating exosome secretion

Background To 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 results In 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. Conclusions Our 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.