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Cancer Res. 2014 Jan 15;74(2):532-42. doi: 10.1158/0008-5472.CAN-13-2203. Epub 2013 Nov 27.

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

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Authors' Affiliations: Experimental and Molecular Pathology, Institute of Pathology; Institute of Pathology, Ludwig-Maximilians-University Munich, Munich; German Cancer Consortium (DKTK); and German Cancer Research Center (DKFZ), Heidelberg, Germany.


The transcription factor AP4 mediates epithelial-mesenchymal transition (EMT) in colorectal cancer 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 colorectal cancer 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' untranslated region (3'-UTR) of AP4 mRNA, induced mesenchymal-epithelial transition (MET), and inhibited colorectal cancer cell migration and invasion. The downregulation of AP4 was necessary for induction of MET and cell cycle arrest 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, which may determine metastatic prowess.

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