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

Mei Xue,Xiang Wang,Ruiqi Wang,Xu Li,Jingjing Pan,An Xiang,Huilian Hou,Huan Pang,Hongli An,Wei Chen,He Chen

doi:10.1186/s12943-017-0714-8

Mei Xue, Xiang Wang + Show 9 more

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https://doi.org/10.1186/s12943-017-0714-8

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Abstract

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.

Highlights

To 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
Identification of exosomes derived from bladder cancer cells cultured under normoxic and hypoxic conditions Bladder cancer cell-derived exosomes were isolated from the conditioned media of 5637 cells cultured under normoxic or hypoxic conditions
There was a difference in the size distribution of exosomes between transmission electron microscopy (TEM) and Nanoparticle tracking analysis (NTA) analyses, and the main reason for such difference might be the aggregation behavior of exosomes in nanoparticle tracking analysis

Summary

Introduction

To 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. RNAs are reported to be the predominant molecular cargos of tumor cell-derived exosomes, and many species of noncoding RNAs including microRNAs (miRNAs) [6], circular RNAs [7] and long non-coding RNAs (lncRNAs) [8] are enriched in these exosomes, which can reflect the dysregulated non-coding RNAs profiles in tumor cells [9] These functional non-coding RNAs delivered by exosomes to a recipient cell can regulate gene expression to promote primary tumor growth and local invasion and to favour the formation of premetastatic or metastatic niches [10,11,12]. The hypoxic tumor cell-derived exosomal noncoding RNAs have been reported to play significant roles in facilitating angiogenesis and dissemination [18, 19]

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