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Stepwise crosstalk between aberrant Nf1, Tp53 and Rb signalling pathways induces gliomagenesis in zebrafish
Luo, Juanjuan1,2; Liu, Pei1; Lu, Chunjiao1; Bian, Wanping2; Su, Dongsheng1,2; Zhu, Chenchen1; Xie, Shaolin2; Pan, Yihang3; Li, Ningning3; Cui, Wei4
2021-02-01
摘要The molecular pathogenesis of glioblastoma indicates that RTK/Ras/PI3K, RB and TP53 pathways are critical for human glioma-genesis. Here, several transgenic zebrafish lines with single or multiple deletions of nf1, tp53 and rb1 in astrocytes, were established to genetically induce gliomagenesis in zebrafish. In the mutant with a single deletion, we found only the nf1 mutation low-efficiently induced tumour incidence, suggesting that the Nf1 pathway is critical for the initiation of gliomagenesis in zebrafish. Combination of mutations, nf1;tp53 and rb1;tp53 combined knockout fish, showed much higher tumour incidences, high-grade histology, increased invasiveness, and shortened survival time. Further bioinformatics analyses demonstrated the alterations in RTK/Ras/PI3K, cell cycle, and focal adhesion pathways, induced by abrogated nf1, tp53, or rb1, were probably the critical stepwise biological events for the initiation and development of gliomagenesis in zebrafish. Gene expression profiling and histological analyses showed the tumours derived from zebrafish have significant similarities to the subgroups of human gliomas. Furthermore, temozolomide treatment effectively suppressed gliomagenesis in these glioma zebrafish models, and the histological responses in temozolomide-treated zebrafish were similar to those observed in clinically treated glioma patients. Thus, our findings will offer a potential tool for genetically investigating gliomagenesis and screening potential targeted anti-tumour compounds for glioma treatment.
关键词nf1 rb1 tp53 glioma zebrafish
DOI10.1093/brain/awaa430
发表期刊BRAIN
ISSN0006-8950
卷号144页码:615-635
通讯作者Pei, De-Sheng(peids@cigit.ac.cn) ; Yang, Xiaojun(yangx@stu.edu.cn)
收录类别SCI
WOS记录号WOS:000649446500034
语种英语