MiR-769-5p of macrophage exosomes induced by GRP78 promotes stemness and chemoresistance in colorectal cancer
Jinmiao Tian, Lichao Zhang, Xiaoqin La, Xiaxia Fan, Zhuoyu Li
Abstract
The tumor microenvironment (TME) plays an important role in tumorigenesis and development. Tumor-associated macrophages (TAMs) are essential members of the TME, the exosomes and miRNAs they secrete are crucial in tumor regulation. Our previous study showed that GRP78-induced macrophages infinitely tend to be M2-type TAMs. In this study, the exosomes of M0 and GRP78-induced macrophage were collected and co-incubated with colorectal cancer (CRC) cells. The results implied that macrophage exosomes induced by GRP78 (GRP78-exos) significantly promoted stemness and chemoresistance in CRC in vitro and in vivo. Further, the top 5 miRNAs upregulated in GRP78-exos were obtained from miRNA sequencing data. The qRT-PCR validation revealed that miR-769-5p was the most observably upregulated and could be directly transferred into CRC cells via GRP78-exos. Mechanistically, the study indicated that miR-769-5p targeted MAPK1 to regulate the cell cycle-related proteins RB1, cyclin D1, and cyclin E1. This contributes to CRC cells entering a quiescent state, which leads to the development of chemoresistance. Moreover, miR-769-5p is also expressed higher in the tissues of 5-FU-resistant CRC patients. In summary, the findings indicate a novel function of miR-769-5p as a potential marker for the diagnosis and treatment of chemotherapy resistance in CRC.