Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway

Oliver A. Kent; Raghu R. Chivukula; Michael Mullendore; Erik A. Wentzel; Georg Feldmann; Kwang H. Lee; Shu Liu; Steven D. Leach; Anirban Maitra; Joshua T. Mendell

doi:10.1101/gad.1950610

Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway

¹Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
²The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
³The Sol Goldman Pancreatic Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
⁴Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
⁵Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
⁶Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
⁷Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
⁸Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Abstract

Although activating mutations in RAS oncogenes are known to result in aberrant signaling through multiple pathways, the role of microRNAs (miRNAs) in the Ras oncogenic program remains poorly characterized. Here we demonstrate that Ras activation leads to repression of the miR-143/145 cluster in cells of human, murine, and zebrafish origin. Loss of miR-143/145 expression is observed frequently in KRAS mutant pancreatic cancers, and restoration of these miRNAs abrogates tumorigenesis. miR-143/145 down-regulation requires the Ras-responsive element-binding protein (RREB1), which represses the miR-143/145 promoter. Additionally, KRAS and RREB1 are targets of miR-143/miR-145, revealing a feed-forward mechanism that potentiates Ras signaling.