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    Keywords: ANGIOGENESIS ; EXPRESSION ; CELL ; GENES ; TUMOR PROGRESSION ; PATHOGENESIS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; MicroRNAs ; MIR-16 FAMILY ; P53 NETWORK
    Abstract: 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
    PubMed ID: 24285725
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