Regulation of EMT and metastasis by mutual inhibition of AP4 and miR-15a/16-1 in colorectal cancer

Shi, Lei (2014): Regulation of EMT and metastasis by mutual inhibition of AP4 and miR-15a/16-1 in colorectal cancer. Dissertation, LMU München: Medizinische Fakultät

Abstract

We recently identified the AP4 transcription factor as a c-MYC-inducible mediator of epithelial-mesenchymal transition/EMT in colorectal cancer (CRC). Here we report that AP4 is down-regulated after DNA damage in a p53-dependent manner. p53 repressed AP4 via inducing the microRNAs miR-15a and miR-16-1, which are encoded by the DLEU2 gene and represent tumor suppressors in chronic lymphocytic leukemia. miR-15a/16-1 acted via a conserved seed-matching sequence in the AP4 3’-UTR. Ectopic miR-15a/16-1 also down-regulated AP4 expression and induced mesenchymal-epithelial transition (MET) of CRC cells. Induction of miR-15a/16-1 was necessary for p53-induced MET and mediated, at least in part, inhibition of migration by p53. Down-regulation of AP4 was necessary for miR-15a/16-1-induced MET and suppression of migration and cell cycle progression. Furthermore, constitutive ectopic expression of miR-15a/16-1 in xeno-transplanted CRC cells suppressed the formation of lung metastases in NOD/SCID mice. In addition, ectopic AP4 suppressed the expression of miR-15a/16-1 by direct occupancy of E-boxes in the vicinity of the two alternative DLEU2 promoters. Finally, expression of miR-15a and DLEU2 was significantly down-regulated in primary colon and colorectal cancer samples, which displayed elevated AP4 protein levels, a marker previously shown to correlate with distant metastasis and poor survival. In conclusion, miR-15a/16-1 and AP4 therefore constitute a double-negative feed-back loop, which may serve to stabilize epithelial and mesenchymal states, respectively. During CRC progression, and presumably in other tumor entities, the deregulation of this circuitry by inactivation of p53 or/and DLEU2, or activation of AP4 may contribute to metastasis.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: EMT, metastasis, p53, miR-15a/16-1, AP4
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 10. November 2014
• 1. Bericht­erstatter:in: Hermeking, Heiko