肿瘤来源的细胞外囊泡包裹的miR-181b-5p诱导血管生成以促进食管鳞状细胞癌的发生和转移。

Tumor-Derived EV-Encapsulated miR-181b-5p Induces Angiogenesis to Foster Tumorigenesis and Metastasis of ESCC.

作者信息

Wang Ying, Lu Jiqiang, Chen Lin, Bian Huan, Hu Jialiang, Li Dongping, Xia Chunlei, Xu Hanmei

机构信息

The Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.

出版信息

Mol Ther Nucleic Acids. 2020 Jun 5;20:421-437. doi: 10.1016/j.omtn.2020.03.002. Epub 2020 Mar 13.

Pathological angiogenesis is necessary for tumor development and metastasis. Tumor-derived extracellular vesicles (EVs) play an important role in mediating the crosstalk between cancer cells and vascular endothelial cells. To date, whether and how microRNAs (miRNAs) encapsulated in tumor-derived EVs affect angiogenesis in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we showed that miR-181b-5p, an angiogenesis-promoting miRNA of ESCC, can be transferred from ESCC cells to vascular endothelial cells via EVs. In addition, ESCC-derived EVs-miR-181b-5p dramatically induced angiogenesis by targeting PTEN and PHLPP2, and thereby facilitated tumor growth and metastasis. Moreover, miR-181b-5p was highly expressed in ESCC tissues and serum EVs. High miR-181b-5p expression level in ESCC patients was well predicted for poor overall survival. Our work suggests that intercellular crosstalk between tumor cells and vascular endothelial cells is mediated by tumor-derived EVs. miR-181b-5p-enriched EVs secreted from ESCC cells are involved in angiogenesis that control metastasis of ESCC, providing a potential diagnostic biomarker or drug target for ESCC patients.

病理性血管生成是肿瘤发展和转移所必需的。肿瘤来源的细胞外囊泡（EVs）在介导癌细胞与血管内皮细胞之间的相互作用中发挥重要作用。迄今为止，肿瘤来源的EVs中包裹的微小RNA（miRNAs）是否以及如何影响食管鳞状细胞癌（ESCC）的血管生成仍不清楚。在此，我们表明，ESCC中一种促进血管生成的miRNA——miR-181b-5p，可以通过EVs从ESCC细胞转移到血管内皮细胞。此外，ESCC来源的EVs-miR-181b-5p通过靶向PTEN和PHLPP2显著诱导血管生成，从而促进肿瘤生长和转移。此外，miR-181b-5p在ESCC组织和血清EVs中高表达。ESCC患者中miR-181b-5p的高表达水平可很好地预测总体生存率较差。我们的研究表明，肿瘤细胞与血管内皮细胞之间的细胞间相互作用是由肿瘤来源的EVs介导的。ESCC细胞分泌的富含miR-181b-5p的EVs参与了控制ESCC转移的血管生成，为ESCC患者提供了一种潜在的诊断生物标志物或药物靶点。