The Long Non-Coding RNA H19 Drives the Proliferation of Diffuse Intrinsic Pontine Glioma with H3K27 Mutation.
The Long Non-Coding RNA H19 Drives the Proliferation of Diffuse Intrinsic Pontine Glioma with H3K27 Mutation.
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DOI：
10.3390/ijms22179165
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发表时间：
2021-08-25
影响因子：
5.6
通讯作者：
Crea F
中科院分区：
文献类型：
--
作者：
Roig-Carles D;Jackson H;Loveson KF;Mackay A;Mather RL;Waters E;Manzo M;Alborelli I;Golding J;Jones C;Fillmore HL;Crea F
弥漫性内在脑桥胶质瘤是一种无法治愈的儿科恶性肿瘤。确定DIPG进展的分子驱动因素至关重要。长链非编码rna （lncRNAs）代表了一个大的疾病和组织特异性转录本家族，其在DIPG中的功能尚未被阐明。本文中，我们研究了发育相关的H19 lncRNA在DIPG中的致癌作用。临床数据集的生物信息学分析用于测量H19 lncRNA在儿科高级别胶质瘤（pedHGGs）中的表达。在DIPG细胞株中验证了H19 lncRNA的表达和亚细胞定位。设计锁定核酸反义寡核苷酸检测H19在DIPG细胞中的功能。我们发现H19在DIPG中的表达高于正常脑组织和其他pedhgg。H19敲低导致DIPG细胞增殖和存活降低。在机制上，H19缓冲let-7 microrna，导致致癌let-7靶点（如SULF2和OSMR）的上调。H19是DIPG中第一个功能表征的lncRNA，也是治疗这种无法治愈的癌症的有希望的治疗候选者。
Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying the molecular drivers of DIPG progression is of the utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not yet been elucidated in DIPG. Herein, we studied the oncogenic role of the development-associated H19 lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression of H19 lncRNA in paediatric high-grade gliomas (pedHGGs). The expression and sub-cellular location of H19 lncRNA were validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function of H19 in DIPG cells. We found that H19 expression was higher in DIPG vs. normal brain tissue and other pedHGGs. H19 knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically, H19 buffers let-7 microRNAs, resulting in the up-regulation of oncogenic let-7 target (e.g., SULF2 and OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate for treating this incurable cancer.
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