Stmc-06. qki deletion enhances self-renewal of glioma stem cells and promotes gliomagenesis

Glioma stem cells (GSCs) have higher self-renewal capacity than neural stem cells (NSCs). However it is still not clear how GSCs enhance their self-renewal and whether or not enhanced self-renewal alone without affecting cell proliferation can promote gliomagenesis. Here we report the generation of a novel conditional KO allele of QKI, a tumor suppressor in GBM with RNA binding motif. When QKI was deleted in NSCs isolated from subventricular zone of Nestin-CreERT2 QKI L/L mice, multiple NSC markers were dramatically increased. When QKI was deleted in adult Nestin-CreERT2 QKI L/L mice, the NSC population, which is characterized by long-term BrdU retention and GFAP+/Nestin+ double positive staining, was greatly increased, indicating that deletion of QKI enhances NSC self-renewal. To determine whether QKI deletion promotes gliomagenesis, we generated a Nestin-CreERT2 QKI L/L Pten L/L P53 L/L cohort, in which 92% of the mice developed glioblastoma starting at 2 months. However, the Nestin-CreERT2 Pten L/L P53 L/L cohort did not develop any glioma up to a year; therefore QKI deletion greatly promotes gliomagenesis. Transcriptomic and proteomic profiling coupled with PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) analyses revealed that genes involved in receptor trafficking were greatly enriched by QKI deletion. Specifically, 34% of the genes up-regulated by QKI deletion are involved in receptor delivery, and 39% of the g...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: STEM CELLS Source Type: research