Reversing epithelial-to-mesenchymal transition (EMT) in cancer cells has been widely considered as an approach to combat cancer progression and therapeutic resistance, but a limited number of broadly comprehensive investigations of microRNAs involved in this process have been conducted. In this study, we screened a library of 1120 microRNA for their ability to transcriptionally activate the E-cadherin gene CDH1 in a promoter reporter assay as a measure of EMT reversal. By this approach, we defined miR-520f as a novel EMT-reversing microRNA. miR-520f expression was sufficient to restore endogenous levels of E-cadherin in cancer cell lines exhibiting strong or intermediate mesenchymal phenotypes. In parallel, miR-520f inhibited invasive behavior in multiple cancer cell systems and reduced metastasis in an experimental mouse model of lung metastasis. Mechanistically, miR-520f inhibited tumor cell invasion by directly targeting ADAM9, the TGF-ß receptor TGFBR2 and the EMT inducers ZEB1, ZEB2 and the snail transcriptional repressor SNAI2, each crucial factors in mediating EMT. Collectively, our results show that miR-520f exerts anti-invasive and anti-metastatic effects in vitro and in vivo, warranting further study in clinical settings.
- Received October 6, 2016.
- Revision received January 25, 2017.
- Accepted January 25, 2017.
- Copyright ©2017, American Association for Cancer Research.