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 CDH1 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 ADAM9, the TGFβ 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 antimetastatic effects in vitro and in vivo, warranting further study in clinical settings. Cancer Res; 77(8); 2008-17. ©2017 AACR.
Highlights
Cancer is a leading cause of death across the world, with the most common type of cancer being carcinoma, which originates from epithelial tissues
As epithelial-tomesenchymal transition (EMT) plays a fundamental role in metastasis, reversing this process may be a promising approach to target metastatic tumor cells
We demonstrated that miR-520f is able to transcriptionally activate CDH1 expression in our screening model
Summary
Cancer is a leading cause of death across the world, with the most common type of cancer being carcinoma, which originates from epithelial tissues. Despite major advances in our understanding of the molecular and genetic basis of cancer, metastasis still causes 90% of all cancer-related deaths, and remains one of most complex and challenging problems of contemporary oncology. Cells lose their epithelial characteristics and gain a more mesenchymal phenotype. This so-called EMT is associated with the ability of cells to migrate and invade into the surrounding tissue. These processes are the first steps toward metastatic spread
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