Oncogenic long noncoding RNA LINC02283 enhances PDGF receptor A-mediated signaling and drives glioblastoma tumorigenesis

PDGFRA公司 PDGFRB公司 癌症研究 癌变 胶质瘤 长非编码RNA 生物 基因敲除 蛋白激酶B PI3K/AKT/mTOR通路 MAPK/ERK通路 信号转导 核糖核酸 癌症 基因 间质细胞 细胞生物学 遗传学 主旨
作者
Anshika Goenka,Xiao Song,Deanna Tiek,Rebeca Piatniczka Iglesia,Minghui Lu,Zeng Chen,Craig Horbinski,Wei Zhang,Bo Hu,Shi‐Yuan Cheng
出处
期刊:Neuro-oncology [Oxford University Press]
卷期号:25 (9): 1592-1604 被引量:1
标识
DOI:10.1093/neuonc/noad065
摘要

Abstract Background Long noncoding RNAs (lncRNAs) regulate the etiology of complex diseases and cancers, including glioblastoma (GBM). However, lncRNA-based therapies are limited because the mechanisms of action of many lncRNAs with their binding partners are not completely understood. Methods We used transcriptomic and genomic data to analyze correlations between LINC02283 and PDGFRA (platelet-derived growth factor receptor A). The biological functions of the novel lncRNA were assessed in vivo using patient-derived glioma stem-like cells (GSCs), and orthotopic GBM xenografts. Immunoblotting, qRT-PCR, RNA pull down, crosslinked RNA immunoprecipitation, fluorescence in situ hybridization, and antisense oligo-mediated knockdown were performed to explore the regulation of LINC02283 on PDGFRA signaling. Expression of LINC02283 in clinical samples was assessed using pathologically diagnosed GBM patient samples. Results We identified a novel oncogenic lncRNA, LINC02283, that is highly expressed in the PDGFRA mutation-driven cohort of glioma patients and associated with worse prognosis. LINC02283 gene co-amplifies with the PDGFRA locus and shows high correlation with PDGFRA expression. Deprivation of LINC02283 in GSCs with PDGFRA amplification mutation, attenuated tumorigenicity and enhanced survival in orthotopic GBM xenograft models, while overexpression of LINC02283 in GSCs with wild-type PDGFRA, enhances PDGFRA signaling, and decreases survival. Further, LINC02283 interacts with PDGFRA to enhance its signaling and that of its downstream targets AKT and ERK, thus promoting oncogenesis in GBM. Conclusions Our results provide strong evidence of LINC02283 as a regulator of PDGFRA oncogenic activity and GBM malignancy and support the potential of lncRNAs as possible therapeutic targets.
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