The lncRNA H19 mediates breast cancer cell plasticity during EMT and MET plasticity by differentially sponging miR-200b/c and let-7b

Abstract

Metastasis is amultistep process bywhich tumor cells disseminate fromtheirprimary site and formsecondary tumors at a distant site. The pathophysiological course of metastasis is mediated by the dynamic plasticity of cancer cells, which enables them to shift between epithelial and mesenchymal phenotypes through a transcriptionally regulated program termed epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET). Using a mouse model of spontaneous metastatic breast cancer, we investigated the molecular mediators ofmetastatic competencewithin a heterogeneous primary tumor and howthese cells thenmanipulated their epithelial-mesenchymal plasticity during themetastatic process.Weisolated cells fromthe primarymammary tumor, the circulation, and metastatic lesions in the lung in TA2mice and found that the long noncoding RNA (lncRNA) H19 mediated EMT andMET by differentially acting as a sponge for themicroRNAs miR-200b/c and let-7b.We found that this ability enabled H19 to modulate the expression of the microRNA targets Git2 and Cyth3, respectively, which encode regulators of the RAS superfamily member adenosine 5′-diphosphate (ADP) ribosylation factor (ARF), a guanosine triphosphatase (GTPase) that promotes cell migration associated with EMT and disseminating tumor cells. Decreasing the abundance of H19 or manipulating that of members in its axis prevented metastasis from grafts in syngeneic mice. Abundance of H19,GIT2, and CYTH3 in patient samples further suggests that H19 might be exploited as a biomarker for metastatic cells within breast tumors and perhaps as a therapeutic target to prevent metastasis.