Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice

Mei-Xin Li, Sheng Hu, He-Hua Lei, Meng Yuan, Xu Li, Wen-Kui Hou, Xiang-Jie Huang, Bing-Wen Xiao, Teng-Xiang Yu, Xiao-Hui Zhang, Xiao-Ting Wu, Wen-Qiang Jing, Hyeon-Jeong Lee, Juan-Juan Li, Da Fu, Li-Min Zhang () and Wei Yan ()
Additional contact information
Mei-Xin Li: Wuhan University
Sheng Hu: Wuhan University
He-Hua Lei: Chinese Academy of Sciences (CAS)
Meng Yuan: Wuhan University
Xu Li: Wuhan University
Wen-Kui Hou: Wuhan University
Xiang-Jie Huang: Zhejiang University
Bing-Wen Xiao: Wuhan University
Teng-Xiang Yu: Wuhan University
Xiao-Hui Zhang: Wuhan University
Xiao-Ting Wu: Wuhan University
Wen-Qiang Jing: Wuhan University
Hyeon-Jeong Lee: Zhejiang University
Juan-Juan Li: Renmin Hospital of Wuhan University
Da Fu: Shanghai Jiaotong University School of Medicine
Li-Min Zhang: Chinese Academy of Sciences (CAS)
Wei Yan: Wuhan University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Cancer cells secrete extracellular vesicles (EV) encapsulating bioactive cargoes to facilitate inter-organ communication in vivo and are emerging as critical mediators of tumor progression and metastasis, a condition which is often accompanied by a dysregulated cholesterol metabolism. Whether EVs are involved in the control of cholesterol homeostasis during tumor metastasis is still undefined and warrant further investigation. Here, we find that breast cancer-derived exosomal miR-9-5p induces the expression of HMGCR and CH25H, two enzymes involved in cholesterol synthesis and the conversion of 25-hydroxycholesterol from cholesterol by targeting INSIG1, INSIG2 and ATF3 genes in the liver. Notably, in vivo miR-9-5p antagomir treatment and genetic CH25H ablation prevents tumor metastasis in a mouse model of breast cancer. Thus, our findings reveal the regulatory mechanism of tumor-derived miR-9-5p in liver metastasis by linking oxysterol metabolism and Kupffer cell polarization, shedding light on future applications for cancer diagnosis and treatment.

Date: 2024
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DOI: 10.1038/s41467-024-54706-z

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