Research ArticleCancer

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

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Sci. Signal.  13 Jun 2017:
Vol. 10, Issue 483, eaak9557
DOI: 10.1126/scisignal.aak9557

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A noncoding mediator of metastasis

To metastasize, cancer cells undergo dynamic shifts in phenotype called epithelial-to-mesenchymal transition (EMT) and its reverse process (MET). These phenotypic shifts are controlled in part by microRNAs (miRNAs), which, by binding to target transcripts, suppress the abundance of various proteins. By isolating tumor cells from the primary site, the circulation, and metastatic nodules in the lung in a mouse model of metastatic breast cancer, Zhou et al. found that the long noncoding RNA (lncRNA) H19 acted as a “sponge” for miRNAs to promote an epithelial or mesenchymal switch in tumor cells. In epithelial-like tumor cells in the primary and metastatic sites, H19 sequestered miR-200b/c, which ultimately inhibited the migration-related protein ARF. In mesenchymal-like, disseminated cells in the circulation, H19 sequestered let-7b, ultimately activating ARF. H19 abundance was greater in metastatic than in nonmetastatic human tumors. These findings reveal a previously unknown mediator of the EMT/MET phenomenon in metastasis.

Abstract

Metastasis is a multistep process by which tumor cells disseminate from their primary site and form secondary 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 of metastatic competence within a heterogeneous primary tumor and how these cells then manipulated their epithelial-mesenchymal plasticity during the metastatic process. We isolated cells from the primary mammary tumor, the circulation, and metastatic lesions in the lung in TA2 mice and found that the long noncoding RNA (lncRNA) H19 mediated EMT and MET by differentially acting as a sponge for the microRNAs 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.

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