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

Shan Wang,Ning Li,Brian D Gregory,Shilpa Rao,Gerard Minuesa,Kimberly Parada,Angela Nakauka-Ddamba,Fan Li,Yarden Katz,Maryam Yousefi,Zhengquan Yu,Michael G Kharas,Christopher J Lengner

doi:10.1038/ncomms7517

Abstract

The MSI2 RNA binding protein is a potent oncogene playing key roles in hematopoietic stem cell homeostasis and malignant hematopoiesis. 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 tumor 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 tumor 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.

Highlights

The MSI2 RNA-binding protein is a potent oncogene playing key roles in haematopoietic stem cell homeostasis and malignant haematopoiesis
Genetic inactivation of the adenomatous polyposis coli (APC) tumour suppressor gene is believed to initiate the majority of human colorectal cancer (CRC), and elegant genetic studies suggest that APC loss only initiates tumorigenesis when it occurs in intestinal stem cell (ISC) with selfrenewal capacity[13]
Genetic inactivation of APC is found in B80% of human patients with CRC, and families harbouring a germline mutation in one APC allele suffer from familial adenomatous polyposis, a disease characterized by the formation of numerous intestinal polyps resulting from stochastic loss of heterozygosity (LOH) at the APC locus, some of which will invariably progress to CRC14–16

Summary

Introduction

The MSI2 RNA-binding protein is a potent oncogene playing key roles in haematopoietic stem cell homeostasis and malignant haematopoiesis. Msi[2] has been implicated as a critical regulator of haematopoietic stem cell (HSC) self-renewal and fate determination and MSI2 is a potent cooperative oncogene in human leukaemias[4,5,6]. MSI2 abrogation in myeloid leukaemia cells increases differentiation, decreases proliferation and increases apoptosis[4] These studies demonstrate that MSI2 cooperates with known oncogenes in haematopoietic malignancies. The putative role of MSI1 in CRC and ISCs, coupled with our past observations of MSI2 function in the HSC and haematopoietic cancers, prompted us to investigate a role of MSI2 in intestinal transformation. The role of MSI2 in this process and its potential interaction with the Wnt signalling pathway remains entirely unknown

Methods

Results

Conclusion