Abstract
Extravasation of circulating cancer cells determines their metastatic potential. This process is initiated by the adhesion of cancer cells to vascular endothelial cells through specific interactions between endothelial adhesion receptors such as E-selectin and their ligands on cancer cells. In the present study, we show that miR-146a and miR-181b impede the expression of E-selectin by repressing the activity of its transcription factor NF-κB, thereby impairing the metastatic potentials of colon cancer cells by decreasing their adhesion to, and migration through, the endothelium. Among the two microRNAs, only miR-146a is activated by IL-1β, through the activation of p38, ERK and JNK MAP kinases, as well as their downstream transcription factors GATA2, c-Fos and c-Jun. Inhibiting p38 MAP kinase increases NF-κB activity, at least partially via miR-146a. Inhibiting p38 also increases the expression of E-selectin at the post-transcriptional level via decreasing miR-31, which targets E-selectin mRNA and also depends on p38 for its expression. In response to IL-1β, p38 MAP kinase hence represses the expression of E-selectin at the transcriptional and the post-transcriptional levels, via miR-146a and miR-31, respectively. These results highlight novel mechanisms by which p38 downregulates the expression of E-selectin through different microRNAs following inflammatory stimuli associated to cancer progression.
Highlights
Metastasis depends on sequential interrelated steps[1]
The effect of miR-146a on the regulation of E-selectin was further confirmed in human liver sinusoidal microvascular endothelial cells (HLSMECs; Supplementary Fig. S1a), but the blockage of miR-181b did not affect E-selectin level in these cells that express very high level of this miRNA (~20 fold more miR-181b detected in HLSMECs compared to human umbilical vein endothelial cells (HUVECs); Supplementary Fig. S1b)
E-selectin interacts with colon cancer cells by binding to various counter-receptors constituted by a scaffold containing the Sialy Lewis a/x tetra-saccharide carbohydrate borne by signalling proteins including CD44v, CEA, PODXL, MUC16 and death receptor 3 (DR3)[2,33,34,35,36,37]
Summary
Metastasis depends on sequential interrelated steps[1]. Notably, the adhesion of circulating cancer cells to the endothelium of blood vessels is a prerequisite for their extravasation. We found that miR-146a and miR-181b inhibit NF-κB-mediated expression of E-selectin and act as potent repressors of E-selectin-dependent metastatic abilities of colon cancer cells.
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