title: 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: 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.
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Rene
authors.initials: R
authors.lastname: Jackstadt
authors.forename: Helge
authors.initials: H
authors.lastname: Siemens
authors.forename: Huihui
authors.initials: H
authors.lastname: Li
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000378:metabolism*; D004268:DNA-Binding Proteins; D058750:Epithelial-Mesenchymal Transition; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; C404766:REPIN1 protein, human; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53