miRNA-520f Reverses Epithelial-to-Mesenchymal Transition by Targeting <i>ADAM9</i> and <i>TGFBR2</i>

Abstract

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 miRNAs involved in this process have been conducted. In this study, we screened a library of 1120 miRNA for their ability to transcriptionally activate the E-cadherin gene <i>CDH1</i> in a promoter reporter assay as a measure of EMT reversal. By this approach, we defined miR-520f as a novel EMT-reversing miRNA. 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 <i>ADAM9</i>, the TGFβ receptor <i>TGFBR2</i> and the EMT inducers <i>ZEB1, ZEB2</i>, and the snail transcriptional repressor <i>SNAI2</i>, each crucial factors in mediating EMT. Collectively, our results show that miR-520f exerts anti-invasive and antimetastatic effects <i>in vitro</i> and <i>in vivo</i>, warranting further study in clinical settings. <i>Cancer Res; 77(8); 2008-17. ©2017 AACR</i>.