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.