The transcription factor AP4 mediates epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) but its control in this setting is not fully understood. Here we report the definition of a double-negative feedback loop involving AP4 and miR-15a/16-1 that regulates EMT and metastatic progression. In CRC cells, AP4 was downregulated by DNA damage in a p53-dependent manner. AP4 downregulation by p53 was mediated indirectly by the tumor suppressive microRNAs miR-15a and miR-16-1, which targeted the 3'-UTR of AP4 mRNA, induced mesenchymal-epithelial transition (MET) and promoted CRC cell migration. However, miR-15a/16-1 also acted downstream of p53 to induce MET and limit CRC cell migration. This latter pathway acted as a negative feedback on AP4, the downregulation of which relied upon MET induction by miR-15a/16-1. In tumor xenoplants, ectopic miR-15a/16-1 suppressed formation of lung metastases whereas ectopic AP4 suppressed expression of miR-15a/16-1. In clinical specimens of colorectal cancer, miR-15a levels inversely correlated with AP4 protein levels shown previously to correlate with distant metastasis and poor survival. In summary, our results define a double-negative feedback loop involving miR-15a/16-1 and AP4 that stabilizes epithelial and mesenchymal states, respectively, that may determine metastatic prowess.
Type of Publication:
Journal article published