Process that occurs during embryonic development, wound healing and cancer metastasis. During EMT, epithelial cells acquire a more mesenchymal phenotype with increased motility and invasiveness and decreased cell-cell adhesion. A key event during this transition is the loss of the epithelial marker E-cadherin. LY2109761 MiR-200 family members have been shown to target the transcription factors ZEB1 and ZEB2 that normally repress the expression of, among other genes, E-cadherin and in this way miR200 microRNAs help to maintain the cell in an epithelial state. It is known that EMT is intimately linked to cancer development and that metastasizing cells undergo a process that is very similar to EMT. However, cancer cells can also undergo the reverse process, 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 whenthe cancer cells become invasive and that this is 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. MiR200c keeps Noxa in check to prevent premature or excessive apoptosis to occur. Once Noxa is induced to high enough levels following cellular stress, the interaction between miR-200c and Noxa becomes lessrelevant and other miR-200c targets play amore 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 amore dominant role inother tissues orwhen Noxais 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 positive effect of miR-200c on apoptosis becomes even more SJN 2511 pronounced, indicating that Noxa indeed potentiates cell death induced by bortezomib. In line with this, ectopic expression of a Noxa construct unresponsive to miR-200c regulation led to potentiation of miR-200c-mediated apoptosis induction. We thus have a situation where the pro-apoptotic effect of miR-200c is partially counteracted by its repressive effect on Noxa. Interestingly, a similar scenario was described for miR-128. It apparently induces apoptosis in HEK293T cells while at the same time it directly represses the pro-apoptotic Bax protein. In conclusion, we have identified miR-200c as an apoptosis regulating microRNA that represses Noxa.