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Mutant p53 increases exosome-mediated transfer of mi R-21-3p and mi R-769-3p to promote pulmonary metastasis

查看全文 作　　者：Qiang [1]Ju;Lina [1]Zhao;Jiajia [1]Gao;Lanping [1]Zhou;Yang [1]Xu;Yulin [1]Sun;Xiaohang [1]Zhao 高影响力作者 机构地区：[1]State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College高影响力机构 出　　处：《Chinese Journal of Cancer Research》索引2019年第31卷第3期,共14页高影响力期刊 基　　金：supported by grants from the National Key R & D Program of China (No. 2017YFC0906601, No. 2017ZX10203205-003-001 and No. 2016YFC0901403);the National Natural Science Foundation (No. 81572840, No. 81572365, No. 81728015 and No. 81872033);the Nonprofit Central Research Institute Fund of CAMS (No. 2018RC310011);the CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-1-001, No. 2017-I2M-3005 and No. 2019-I2M-1-003) in China 摘　　要：Objective: Tumor metastasis is a complex, multistep process that depends on tumor cells and their communication with the tumor microenvironment. A p53 gain-of-function mutant has been shown to enhance the tumorigenesis, invasion, and metastasis abilities of tumor cells. This study aimed to investigate the roles of p53 R273 H mutation in the tumor microenvironment.Methods: The in vitro and in vivo effects of the p53 R273 H mutant on the invasion and metastasis of HCT116 cells were investigated. Exosomes from wild-type and HCT116-TP53(R273 H) cells were cocultured with mouse embryonic fibroblasts(MEFs). The roles of differentially expressed exosomal micro RNAs identified by microarray analysis were investigated. The functions of the p53 R273 H mutant in tumor cells were also investigated via gene expression microarray and quantitative polymerase chain reaction(q PCR) analyses.Results: Introducing p53 R273 H mutant into HCT116 cells significantly potentiated pulmonary metastasis in vivo. In the presence of exosomes derived from HCT116-TP53(R273 H) cells, the exosomes were taken up by MEFs and became activated. Microarray analysis showed that the p53 R273 H mutation increased the exosomal levels of mi R-21-3 p and mi R-769-3 p. Intriguingly, in clinical samples, mi R-21-3 p and mi R-769-3 p levels were significantly higher in patients with a p53 mutation than in those without this mutation. Furthermore, both mi R-21-3 p and mi R-769-3 p activated fibroblasts and exerted a synergistic effect via their target genes on the transforming growth factor-β(TGF-β)/Smad signaling pathway. The activated fibroblasts excreted cytokine TGF-β and may have reciprocally induced cancer cells to undergo epithelial-mesenchymal transition(EMT). Indeed, HCT116-TP53(R273 H) cells showed increased expression of ZEB1 and SNAI2 and decreased transcription of several cell adhesion molecules.Conclusions: The mutant p53-exosomal mi R-21-3 p/mi R-769-3 p-fibroblast-cytokine circuit appears to be responsible for communication between tumor and stromal cells, with exosomal mi RNAs acting as a bridge. mi R-21-3 p and mi R-769-3 p are potential predictive markers of pulmonary metastasis and candidate targets for therapeutic interventions. 关 键 词：miR-21-3p miR-769-3p EXOSOME TUMOR metastasis TUMOR MICROENVIRONMENT
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