Liver metastasis (LM) severely affects gastric cancer (GC) patients’ prognosis. Small extracellular vesicles (sEVs) play key roles in intercellular communication. Specific sEV-miRNAs from several types of cancer were found to induce a premetastatic niche in target organs before tumor cell arrive. However, whether the primary GC affects hepatic microenvironment or the role of sEV-miRNAs in GC-LM is yet unclear. We report that GC-derived sEVs are primarily absorbed by Kupffer cells (KCs). sEV-miR-151a-3p is highly expressed in GC-LM patients’ plasma and presents poor prognosis. Treating mice with sEVs-enriched in miR-151a-3p promotes GC-LM, whereas has no influence on the proliferation of GC cells in situ. Mechanistically, sEV-miR-151a-3p inhibits SP3 in KCs. Simultaneously, sEV-miR-151a-3p targets YTHDF3 to decrease the transcriptional inhibitory activity of SP3 by reducing SUMO1 translation in a N6-methyladenosine-dependent manner. These factors contribute to TGF-β1 transactivation in KCs, subsequently activating the SMAD2/3 pathway and enhancing the stem cell-like properties of incoming GC cells. Furthermore, sEV-miR-151a-3p induces miR-151a-3p transcription in KCs to form a positive feedback loop. In summary, our results reveal a previously unidentified regulatory axis initiated by sEV-miR-151a-3p that establishes a hepatic stemness-permissive niche to support GC-LM. sEV-miR-151a-3p could be a promising diagnostic biomarker and preventive treatment candidate for GC-LM.
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The sEV-miRNA-seq and mRNA-seq data that support the findings of this study have been deposited in the SRA database from NCBI with the accession code PRJNA648286. The YTHDF3-CLIP-seq and YTHDF3-RIP-seq and meRIP-seq were downloaded from GEO database with the dataset ID: GSE86214; GSE130171; GSE130172. All other data are available in the article and its additional files or from the corresponding author upon request.
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This work was partially supported by the National Natural Science Foundation of China (81871946, 82002558, 82072708); Special Foundation for National Science and Technology Basic Research Program of China (2019FY101104); the Primary Research & Development Plan of Jiangsu Province (BE2016786); the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU; the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, JX10231801); Jiangsu Key Medical Discipline (General Surgery) (ZDXKA2016005); Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University. We would like to express our gratitude to Dr Xiaofei Zhi and Dr Zheng Chen for their valuable advice on our study. We also thank Prof. Xinyu Xu for her help on FACS experiments.
The authors declare no competing interests.
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Li, B., Xia, Y., Lv, J. et al. miR-151a-3p-rich small extracellular vesicles derived from gastric cancer accelerate liver metastasis via initiating a hepatic stemness-enhancing niche. Oncogene 40, 6180–6194 (2021). https://doi.org/10.1038/s41388-021-02011-0