The lncRNA TP73-AS1 is linked to aggressiveness in glioblastoma and promotes temozolomide resistance in glioblastoma cancer stem cells

被引:126
作者
Mazor, Gal [1 ]
Levin, Liron [2 ]
Picard, Daniel [3 ,4 ,5 ,6 ]
Ahmadov, Ulvi [3 ,4 ,5 ,6 ]
Caren, Helena [7 ]
Borkhardt, Arndt [4 ]
Reifenberger, Guido [5 ]
Leprivier, Gabriel [4 ]
Remke, Marc [3 ,4 ,5 ,6 ]
Rotblat, Barak [1 ]
机构
[1] Ben Gurion Univ Negev, Dept Life Sci, Beer Sheva, Israel
[2] Ben Gurion Univ Negev, Bioinformat Core Facil, Natl Inst Biotechnol Negev, Beer Sheva, Israel
[3] German Canc Res Ctr, Dept Pediat Neurooncogen, Heidelberg, Germany
[4] Univ Hosp Dusseldorf, Fac Med, Dept Pediat Oncol Hematol & Clin Immunol, Dusseldorf, Germany
[5] Univ Hosp Dusseldorf, Inst Neuropathol, Fac Med, Dusseldorf, Germany
[6] German Canc Consortium DKTK, Partner Site Essen Dusseldorf, Dusseldorf, Germany
[7] Univ Gothenburg, Sahlgrenska Acad, Sahlgrenska Canc Ctr, Dept Pathol,Inst Biomed, Gothenburg, Sweden
基金
以色列科学基金会;
关键词
LONG NONCODING RNAS; ALDEHYDE DEHYDROGENASE; ADJUVANT TEMOZOLOMIDE; GENE-EXPRESSION; TRANSCRIPTION; P73; DIFFERENTIATION; RADIOTHERAPY; MAINTENANCE; METHYLATION;
D O I
10.1038/s41419-019-1477-5
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Glioblastoma multiform (GBM) is the most common brain tumor characterized by a dismal prognosis. GBM cancer stem cells (gCSC) or tumor-initiating cells are the cell population within the tumor-driving therapy resistance and recurrence. While temozolomide (TMZ), an alkylating agent, constitutes the first-line chemotherapeutic significantly improving survival in GBM patients, resistance against this compound commonly leads to GBM recurrence and treatment failure. Although the roles of protein-coding transcripts, proteins and microRNA in gCSC, and therapy resistance have been comprehensively investigated, very little is known about the role of long noncoding RNAs (lncRNAs) in this context. Using nonoverlapping, independent RNA sequencing and gene expression profiling datasets, we reveal that TP73-AS1 constitutes a clinically relevant lncRNA in GBM. Specifically, we demonstrate significant overexpression of TP73-AS1 in primary GBM samples, which is particularly increased in the gCSC. More importantly, we demonstrate that TP73-AS1 comprises a prognostic biomarker in glioma and in GBM with high expression identifying patients with particularly poor prognosis. Using CRISPRi to downregulate our candidate lncRNA in gCSC, we demonstrate that TP73-AS1 promotes TMZ resistance in gCSC and is linked to regulation of the expression of metabolism- related genes and ALDH1A1, a protein known to be expressed in cancer stem cell markers and protects gCSC from TMZ treatment. Taken together, our results reveal that high TP73-AS1 predicts poor prognosis in primary GBM cohorts and that this lncRNA promotes tumor aggressiveness and TMZ resistance in gCSC.
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页数:14
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