Research Paper Volume 13, Issue 7 pp 9613—9626

Hypoxia-induced microRNA-155 overexpression in extracellular vesicles promotes renal cell carcinoma progression by targeting FOXO3

Liwei Meng1, , Zhaoquan Xing1, , Zhaoxin Guo1, , Yue Qiu1, , Zhaoxu Liu1,2, ,

  • 1 Department of Urology, Qilu Hospital of Shandong University, Jinan 250000, China
  • 2 School of Nursing, Shandong University, Jinan 250000, China

Received: March 18, 2020       Accepted: February 8, 2021       Published: March 19, 2021
How to Cite

Copyright: © 2021 Meng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Renal cell carcinoma (RCC) is a form of cancer arising from the renal epithelium, with high mortality rates that have reached stable levels over the past decade. The tumor microenvironment is an essential regulator of tumor progression and survival, and extracellular vesicles (EVs) are an important facet of this microenvironment. Herein, we explored the impact of hypoxia-induced miR-155 expression in EVs on FOXO3 expression in RCC cells and their associated oncogenic activity. We found that RCC patients exhibited elevated miR-155 expression in EVs relative to healthy controls, suggesting that this miRNA may be important in the context of RCC progression. We then characterized EVs produced from RCC cell lines (Caki-1 and 786-O) under normoxic and hypoxic conditions, revealing that hypoxia-induced EVs contained higher levels of miR-155 and promoted cell proliferation. Then, we identified FOXO3 as a miR-155 target. Lastly, hypoxia-induced EVs were found to be able to significantly inhibit FOXO3 activation via facilitating miR-155 up-regulation. Together, these findings indicate that hypoxia can promote the upregulation of miR-155 in EVs and that this miRNA can act in RCC cells to suppress FOXO3 expression, thereby enhancing cellular tumor progression.


CD9: Cluster of differentiation 9; EV: Extracellular vesicle; FOXO3: Forkhead box O3; miRNA: MicroRNAs; RCC: Renal cell carcinoma; siRNA: Small interfering RNA; TSG101: Tumor susceptibility protein 101.