The pdgfra-regulating lncrna linc02283 is amplified in high-grade glioma and facilitates gliomagenesis

Abstract Long non-coding RNAs (lncRNAs) regulate numerous physiological processes and the etiology of diseases including cancers. However, lncRNA-based therapies are limited because the mechanism of action of many lncRNAs and their interaction with binding partners is not completely understood. We have identified LINC02283, a novel oncogenic lncRNA, highly expressed in the PDGF Receptor A (PDGFRA)-mutation driven cohort of high-grade glioma (HGG) patients which accounts for ~8% of glioma cases. LINC02283 gene co-amplifies with the PDGFRA locus and is upregulated in HGG. LINC02283 expression and copy number variation were highly correlated to that of PDGFRA expression and amplification respectively, and high LINC02283 levels leads to worse survival in HGG patients. We found that LINC02283 transcription is essential for the survival of Glioma Stem cells (GSCs) with PDGFRA amplification mutation, and its inhibition significantly improves survival in orthotopic HGG xenograft models. Interestingly, overexpression of LINC02283 in GSCs with wild type (wt) - PDGFRA, enhance PDGFRA signaling, increases cell proliferation and worsens survival in orthotopic HGG xenograft models. Inhibition of PDGFRA signaling using AG1296, represses the high endogenous LINC02283 levels in PDGFRA-mutant GSCs, reduces LINC02283 induced signaling in PDGFRA-wt GSCs, and suppresses cell proliferation in both the cellular models of HGG. Moreover, LINC02283 co-localizes and interacts with the wild-type and mutant PDGFRA to enhance its signaling and that of its downstream targets Akt and Erk. In a feedback regulation, dysregulated PDGFRA signaling induces LINC02283 levels to enhance cell proliferation in GSC and GBM cellular models through activating its downstream, Akt and Erk signaling pathways, as their inhibition reduces the lncRNA induction and function. Thus, blocking the LINC02283-PDGFRA interaction could be a plausible therapeutic strategy in HGG. Altogether, our results provide strong evidence of lncRNAs as drivers of PDGF Receptor A activity and HGG progression and support the potential of lncRNAs as possible therapeutic targets.