Transformation of the intestinal epithelium by the MSI2 RNA-binding protein

Shan Wang, Ning Li, Maryam Yousefi, Angela Nakauka-Ddamba, Fan Li, Kimberly Parada, Shilpa Rao, Gerard Minuesa, Yarden Katz, Brian D. Gregory, Michael G. Kharas, Zhengquan Yu () and Christopher J. Lengner ()
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Shan Wang: State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University
Ning Li: School of Veterinary Medicine, University of Pennsylvania
Maryam Yousefi: School of Veterinary Medicine, University of Pennsylvania
Angela Nakauka-Ddamba: School of Veterinary Medicine, University of Pennsylvania
Fan Li: School of Arts and Sciences, University of Pennsylvania
Kimberly Parada: School of Veterinary Medicine, University of Pennsylvania
Shilpa Rao: PENN Molecular Profiling Facility, University of Pennsylvania
Gerard Minuesa: Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center
Yarden Katz: The Broad Institute of Harvard and MIT
Brian D. Gregory: School of Arts and Sciences, University of Pennsylvania
Michael G. Kharas: Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center
Zhengquan Yu: State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University
Christopher J. Lengner: School of Veterinary Medicine, University of Pennsylvania

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: Abstract The MSI2 RNA-binding protein is a potent oncogene playing key roles in haematopoietic stem cell homeostasis and malignant haematopoiesis. Here we demonstrate that MSI2 is expressed in the intestinal stem cell compartment, that its expression is elevated in colorectal adenocarcinomas, and that MSI2 loss-of-function abrogates colorectal cancer cell growth. MSI2 gain-of-function in the intestinal epithelium in a drug-inducible mouse model is sufficient to phenocopy many of the morphological and molecular consequences of acute loss of the APC tumour suppressor in the intestinal epithelium in a Wnt-independent manner. Transcriptome-wide RNA-binding analysis indicates that MSI2 acts as a pleiotropic inhibitor of known intestinal tumour suppressors including Lrig1, Bmpr1a, Cdkn1a and Pten. Finally, we demonstrate that inhibition of the PDK–AKT–mTORC1 axis rescues oncogenic consequences of MSI2 induction. Taken together, our findings identify MSI2 as a central component in an unappreciated oncogenic pathway promoting intestinal transformation.

Date: 2015
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DOI: 10.1038/ncomms7517

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