Abstract 1136: p53-induced miR-15a/16-1 and AP4 form a double-negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal cancer

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 inhibited CRC cell migration and invasion. The downregulation of AP4 was necessary for MET induction by miR-15a/16-1. In tumor xenoplants, ectopic miR-15a/16-1 suppressed formation of lung metastases. Furthermore, AP4 directly 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. Citation Format: Lei Shi, Rene Jackstadt, Helge Siemens, Huihui Li, Thomas Kirchner, Heiko Hermeking. p53-induced miR-15a/16-1 and AP4 form a double-negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1136. doi:10.1158/1538-7445.AM2014-1136