<br>长非编码 RNA OTX2-AS1 促进肿瘤生长并预测髓母细胞瘤对 BCL-2 抑制的反应,Journal of Neuro-Oncology

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长非编码 RNA OTX2-AS1 促进肿瘤生长并预测髓母细胞瘤对 BCL-2 抑制的反应
Journal of Neuro-Oncology ( IF 3.2 ) Pub Date : 2023-11-17 , DOI: 10.1007/s11060-023-04508-y
Nan Qin _{1,

2,

3,

4,

5} , Eunice Paisana ₆ , Daniel Picard _{2,

3} , Gabriel Leprivier ₃ , Maike Langini _{7,

8} , Carlos Custódia ₆ , Rita Cascão ₆ , Catleen Conrad ₇ , Mirko Peitzsch ₇ , Anja Stefanski _{8,

9} , Kai Stühler _{8,

9} , Ute Fischer ₂ , Claudia C Faria _{6,

10} , Sascha Dietrich ₁ , Guido Reifenberger _{3,

11} , Marc Remke _{2,

3,

4,

12}

Affiliation

Department of Hematology, Oncology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.
Institute of Neuropathology, Medical Faculty, Heinrich Heine University, and University Hospital Düsseldorf, Düsseldorf, Germany.
High-Throughput Drug Screening Core Facility, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Düsseldorf, Germany.
Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina da Universidade de Lisboa, Lisbon, 1649-028, Portugal.
Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty Carl Gustav Carus, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Molecular Proteomics Laboratory, Biological and Medical Research Center (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Institute for Molecular Medicine 1, Heinrich Heine University Medical Faculty, Düsseldorf, Germany.
Department of Neurosurgery, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte, EPE, Lisbon, 1649-028, Portugal.
German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.
Department of Pediatric Hematology and Oncology, University Medical Center of Saarland, Homburg/Saar, Germany.

目的

原发性脑肿瘤是儿童癌症相关死亡的主要原因，而髓母细胞瘤是最常见的恶性小儿脑肿瘤。目前髓母细胞瘤的分子特征主要基于蛋白质编码基因，而对于长非编码RNA（lncRNA）的参与知之甚少。本研究旨在阐明 lncRNA OTX2-AS1在髓母细胞瘤中的作用。

方法

对 DNA 拷贝数变化、甲基化谱和基因表达数据的分析用于表征髓母细胞瘤组织样本中OTX2-AS1的分子变化。为了表征OTX2-AS1的功能，进行了髓母细胞瘤细胞模型的体外分析和原位体内实验。采用高通量药物筛选来鉴定药理抑制剂，同时进行蛋白质组学和代谢组学分析来解决药物作用的潜在机制。

结果

我们在髓母细胞瘤亚型中检测到OTX2和OTX2-AS1的扩增和连续过表达。此外， OTX2-AS1启动子甲基化与OTX2-AS1表达相关。 OTX2-AS1敲除降低了体外髓母细胞瘤细胞的活力和细胞迁移，并延长了 D283 原位髓母细胞瘤小鼠异种移植模型的生存期。 BCL-2 的药理抑制可抑制体外过表达OTX2-AS1的髓母细胞瘤细胞的生长。

结论

我们的研究揭示了OTX2-AS1在髓母细胞瘤中的促肿瘤作用，并确定 BCL-2 抑制是针对OTX2-AS1过表达髓母细胞瘤细胞的潜在治疗方法。

"点击查看英文标题和摘要"

The long non-coding RNA OTX2-AS1 promotes tumor growth and predicts response to BCL-2 inhibition in medulloblastoma

Purpose

Primary brain tumors are a leading cause of cancer-related death in children, and medulloblastoma is the most common malignant pediatric brain tumor. The current molecular characterization of medulloblastoma is mainly based on protein-coding genes, while little is known about the involvement of long non-coding RNAs (lncRNAs). This study aimed to elucidate the role of the lncRNA OTX2-AS1 in medulloblastoma.

Methods

Analyses of DNA copy number alterations, methylation profiles, and gene expression data were used to characterize molecular alterations of OTX2-AS1 in medulloblastoma tissue samples. In vitro analyses of medulloblastoma cell models and orthotopic in vivo experiments were carried out for functional characterization of OTX2-AS1. High-throughput drug screening was employed to identify pharmacological inhibitors, while proteomics and metabolomics analyses were performed to address potential mechanisms of drug action.

Results

We detected amplification and consecutive overexpression of OTX2 and OTX2-AS1 in a subset of medulloblastomas. In addition, OTX2-AS1 promoter methylation was linked to OTX2-AS1 expression. OTX2-AS1 knockout reduced medulloblastoma cell viability and cell migration in vitro and prolonged survival in the D283 orthotopic medulloblastoma mouse xenograft model. Pharmacological inhibition of BCL-2 suppressed the growth of OTX2-AS1 overexpressing medulloblastoma cells in vitro.

Conclusions

Our study revealed a pro-tumorigenic role of OTX2-AS1 in medulloblastoma and identified BCL-2 inhibition as a potential therapeutic approach to target OTX2-AS1 overexpressing medulloblastoma cells.

更新日期：2023-11-18

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