RESUMEN
Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers.
Asunto(s)
Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Transformación Celular Neoplásica , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Femenino , Genes Reporteros , Células HCT116 , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Noqueados , Ratones Desnudos , Ratones Transgénicos , Complejos Multiproteicos/metabolismo , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Interferencia de ARN , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/genética , Serina-Treonina Quinasas TOR/metabolismo , Trasplante Heterólogo , beta Catenina/antagonistas & inhibidores , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
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.
