Figure 6

A proposed model for HA/CD44-mediated JNK/c-Jun signaling in the regulation of miRNA-21 production, oncogenesis and chemoresistence in MDA-MB-468 cells. We propose that HA-CD44 binding (step 1) promotes JNK and c-Jun (also serine phosphorylated JNK/c-Jun) (step 2). Subsequently, c-Jun (also p-c-Jun) translocates from the cytosol to the nucleus and interacts with an upstream/enhancer region (containing AP1 binding sites) of the miR-21 promoter (step 3), resulting in miR-21 gene expression (step 4) and mature miR-21 production (step 5). The resultant miR-21 then functions to upregulate the survival protein, Bcl2 (step 6a) and promotes MDA-MB-468 cell activation leading to IAP (c-IAP-1, c-IAP-2 and XIAP) expression (step 7a), MDA-MB-468 cell anti-apoptosis/survival and chemoresistance. In direct contrast, treatment of MDA-MB-468 cells with an anti-miR-21 inhibitor reduces Bcl2 upregulation (step 6b). Subsequently, these changes result in the inhibition of IAP (c-IAP-1, c-IAP-2 and XIAP) expression (step 7b), stimulation of apoptosis and enhancement of chemosensitivity in MDA-MB-468 cells. Taken together, these findings suggest that targeting HA/CD44-mediated JNK/c-Jun signaling pathways and miR-21 function may provide a new drug target to sensitize tumor cell apoptosis/death and overcome chemotherapy resistance in MDA-MB-468 breast tumor cells.