Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1

Molecular Cancer

Research

Mei Xue¹  Hongli An¹  Xu Li¹  He Chen¹  Xiang Wang¹  Ruiqi Wang¹  Wei Chen²  Huan Pang²  Jingjing Pan²  Huilian Hou³  An Xiang⁴ 

[1] Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China;Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China;Department of Clinical Laboratory, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China;Department of Pathology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China;Department of Pharmacology, Fourth Military Medical University, Xi’an, People’s Republic of China;

关键词: Exosomes;    LncRNA-UCA1;    Hypoxia;    Bladder cancer;   

DOI  :  10.1186/s12943-017-0714-8

 received in 2017-02-28, accepted in 2017-08-21,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundTo overcome the hostile hypoxic microenvironment of solid tumors, tumor cells secrete a large number of non-coding RNA-containing exosomes that facilitate tumor development and metastasis. However, the precise mechanisms of tumor cell-derived exosomes during hypoxia are unknown. Here, we aim to clarify whether hypoxia affects tumor growth and progression by transferring long non-coding RNA-urothelial cancer-associated 1 (lncRNA-UCA1) enriched exosomes secreted from bladder cancer cells.MethodsWe used bladder cancer 5637 cells with high expression of lncRNA-UCA1 as exosome-generating cells and bladder cancer UMUC2 cells with low expression of lncRNA-UCA1 as recipient cells. Exosomes derived from 5637 cells cultured under normoxic or hypoxic conditions were isolated and identified by transmission electron microscopy, nanoparticle tracking analysis and western blotting analysis. These exosomes were co-cultured with UMUC2 cells to evaluate cell proliferation, migration and invasion. We further investigated the roles of exosomal lncRNA-UCA1 derived from hypoxic 5637 cells by xenograft models. The availability of lncRNA-UCA1 in serum-derived exosomes as a biomarker for bladder cancer was also assessed.ResultsWe found that hypoxic exosomes derived from 5637 cells promoted cell proliferation, migration and invasion, and hypoxic exosomal RNAs could be internalized by three bladder cancer cell lines. Importantly, lncRNA-UCA1 was secreted in hypoxic 5637 cell-derived exosomes. Compared with normoxic exosomes, hypoxic exosomes derived from 5637 cells showed the higher expression levels of lncRNA-UCA1. Moreover, Hypoxic exosomal lncRNA-UCA1 could promote tumor growth and progression though epithelial-mesenchymal transition, in vitro and in vivo. In addition, the expression levels of lncRNA-UCA1 in the human serum-derived exosomes of bladder cancer patients were higher than that in the healthy controls.ConclusionTogether, our results demonstrate that hypoxic bladder cancer cells remodel tumor microenvironment to facilitate tumor growth and development though secreting the oncogenic lncRNA-UCA1-enriched exosomes and exosomal lncRNA-UCA1 in human serum has the possibility as a diagnostic biomarker for bladder cancer.

【 授权许可】

CC BY   
© The Author(s). 2017