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

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.