This have reported that the miR-200 microRNAs are potent regulators of epithelial-to-mesenchymal transition, a MCE Chemical SP600125 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. MiR-200 Methionine enkephalin 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 miR- 200 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, 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 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 cellular stress, the interaction bet
