Abstract
Epithelial–mesenchymal transitions (EMTs) are high-profile in the field of circulating tumor cells (CTCs). EMT-shifted CTCs are considered to encompass pre-metastatic subpopulations though underlying molecular mechanisms remain elusive. Our previous work identified tissue factor (TF) as an EMT-induced gene providing tumor cells with coagulant properties and supporting metastatic colonization by CTCs. We here report that vimentin, the type III intermediate filament considered a canonical EMT marker, contributes to TF regulation and positively supports coagulant properties and early metastasis. Different evidence further pointed to a new post-transcriptional regulatory mechanism of TF mRNA by vimentin: (1) vimentin silencing accelerated TF mRNA decay after actinomycin D treatment, reflecting TF mRNA stabilization, (2) RNA immunoprecipitation revealed enriched levels of TF mRNA in vimentin immunoprecipitate, (3) TF 3′-UTR-luciferase reporter vector assays implicated the 3′-UTR of TF mRNA in vimentin-dependent TF regulation, and (4) using different TF 3′UTR-luciferase reporter vectors mutated for potential miR binding sites and specific Target Site Blockers identified a key miR binding site in vimentin-dependent TF mRNA regulation. All together, these data support a novel mechanism by which vimentin interferes with a miR-dependent negative regulation of TF mRNA, thereby promoting coagulant activity and early metastasis of vimentin-expressing CTCs.
Highlights
These authors contributed : Marie-Emilie Francart, Aline M
We identified an Epithelial–mesenchymal transitions (EMTs)-driven axis leading to the overexpression of tissue factor (TF), and providing tumor cells with coagulant properties that facilitate early metastatic colonization of circulating tumor cells (CTCs) in experimental metastasis mice assays [21]. Based on this previous work emphasizing a narrow association between vimentin and TF expression in vitro, in human breast cancers and in CTCs isolated from metastatic breast cancer patients, we examined here the possibility that the canonical EMT marker vimentin could directly contribute to TF regulation, and thereby to early metastasis
TF expression was more shown to correlate with vimentin expression in in vitro models of EMT, in human breast cancers and in CTCs isolated from metastatic breast cancer patients [21]
Summary
These authors contributed : Marie-Emilie Francart, Aline M. We identified an EMT-driven axis leading to the overexpression of TF, and providing tumor cells with coagulant properties that facilitate early metastatic colonization of CTCs in experimental metastasis mice assays [21] Based on this previous work emphasizing a narrow association between vimentin and TF expression in vitro, in human breast cancers and in CTCs isolated from metastatic breast cancer patients, we examined here the possibility that the canonical EMT marker vimentin could directly contribute to TF regulation, and thereby to early metastasis. Digging further the mechanisms underlying this regulation, vimentin was found to counteract a miR-dependent negative regulation of TF mRNA
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