Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice
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.
Authors
- Xiang-Jie Huang
- Tinghe Yu
- Xiaoting Wu (ORCID: https://orcid.org/0000-0002-3996-868X)
- Hyeon Jeong Lee (ORCID: https://orcid.org/0000-0002-2417-9338)
- Wei Yan (ORCID: https://orcid.org/0000-0003-3978-7675)
- Wen-Kui Hou
- Meixin Li (ORCID: https://orcid.org/0000-0003-3703-9139)
- Xiaohui Zhang (ORCID: https://orcid.org/0000-0002-4303-7466)
- Yuan Meng (ORCID: https://orcid.org/0009-0003-3001-5799)
- Limin Zhang (ORCID: https://orcid.org/0000-0001-5689-948X)
- Wei Jing (ORCID: https://orcid.org/0000-0002-0573-2783)
- Li Xu (ORCID: https://orcid.org/0000-0003-2721-0377)
- Juanjuan Li (ORCID: https://orcid.org/0000-0002-4165-5981)
- 大崎 往夫 (ORCID: https://orcid.org/0000-0002-4403-3491)
- Bingxiu Xiao (ORCID: https://orcid.org/0000-0002-8592-9251)
- Sheng Hu (ORCID: https://orcid.org/0000-0002-8545-4161)
- H. Lei
Institutions
- Chinese Academy of Sciences (CN)
- Ruijin Hospital (CN)
- Wuhan University (CN)
- Wuhan Institute of Physics and Mathematics (CN)
- Renmin Hospital of Wuhan University (CN)
- University of Chinese Academy of Sciences (CN)
- Hubei University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1038/s41467-024-54706-z
- Citations
- 27
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 6.31
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- Ministry of Science and Technology of the People's Republic of China
- Wuhan University
- Soochow University
- State Key Laboratory of Virology
- Renmin Hospital of Wuhan University