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


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.

Nature Communications (2015)