Cells can also undergo the reverse process, mesenchymal-to-epithelial transition, when colonizing distant sites in the body following extravasation. In light of this it is perhaps not surprising that a complex picture emerges with regard to cancer and miR-200. While many tumor types, such as advanced breast cancer and clear cell carcinoma, show reduced miR-200 levels, some other malignancies instead display overexpressed miR-200 levels. One speculative possibility is that downregulation of miR-200 occurs in some tumors when the cancer cells become invasive and that this is NSC 697286 followed by miR-200 upregulation in distant metastases that undergo MET. While the novel miR-200c target Noxa is dispensable for certain types of cell death, it is crucial for cell death in response to proteasomal inhibition. The proteasome inhibitor bortezomib has been demonstrated to be clinically beneficial in the treatment of multiple tumor types, including myeloma and mantle cell lymphoma. We therefore chose to study its impact in relation to miR-200c. The observed effects of miR-200c on Noxa and cell death induced by bortezomib and other agents might at first appear counterintuitive. Why would miR-200c potentiate apoptosis and repress Noxa at the same time? One possible reason is that is a matter of threshold. MiR- 200c keeps Noxa in check to prevent premature or excessive apoptosis to occur. Once Noxa is induced to high enough levels following 4EGI-1 structure cellular stress, the interaction between miR-200c and Noxa becomes less relevant and other miR-200c targets play a more important role. Indeed, several targets have been described that could explain the pro-apoptotic effect of miR-200c, such as FAP-1, PLCc1 and the above-mentioned ZEB1. In line with this, miR-200c has been described to potentiate apoptosis in response to CD95 signaling and microtubule-targeting agents. Also, it is possible that the miR-200c:Noxa interaction plays a more dominant role in other tissues or when Noxa is induced by other stimuli. One has to bear in mind that the phenotypic effect of a given microRNA is dictated by the sum total expression of all its potential targets. Yet another possibility would be that Noxa for some reason has an anti-apoptotic effect in our systems. However, without Noxa expression, the posi
