In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma
Menée sur un modèle murin de mélanome induit par une mutation du gène BRAF, cette étude identifie le rôle d'un micro-ARN, ZEB2, dans la régulation de l'activité de suppression de tumeurs exercée par PTEN
We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAFV600E to promote melanomagenesis. º A Sleeping Beauty screen followed by MuTaME analysis discovered putative PTEN ceRNAs º The PTEN ceRNA ZEB2 regulates PTEN in a miRNA-independent manner º ZEB2 loss activates PI3K/AKT signaling and promotes cell transformation º Attenuated ZEB2 expression is found in melanoma and other human cancers A transposon-based mutagenesis screen uncovers a striking enrichment of putative PTEN ceRNAs among mutated genes that accelerate tumorigenesis in a mouse model of melanoma. One candidate gene, ZEB2, regulates PI3K/AKT signaling and tumor-suppressive properties of PTEN.
Cell 2011