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Abstract：
OBJECTIVE: 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.
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.
摘要：
目的：原发性脑肿瘤是儿童癌症相关死亡的主要原因，髓母细胞瘤是小儿最常见的恶性脑肿瘤。目前髓母细胞瘤的分子特征主要基于蛋白质编码基因，而对长链非编码RNA（lncRNA）的参与知之甚少。本研究旨在阐明lncRNAOTX2-AS1在髓母细胞瘤中的作用。
方法：分析DNA拷贝数改变，甲基化谱，和基因表达数据用于表征髓母细胞瘤组织样品中OTX2-AS1的分子改变。进行髓母细胞瘤细胞模型的体外分析和原位体内实验以表征OTX2-AS1的功能。高通量药物筛选用于确定药物抑制剂，同时进行蛋白质组学和代谢组学分析以探讨药物作用的潜在机制。
结果：我们在一组髓母细胞瘤中检测到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敲除在D283原位髓母细胞瘤小鼠异种移植模型中降低髓母细胞瘤细胞活力和细胞迁移并延长存活。BCL-2的药理学抑制抑制了体外过表达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发生作用，并确定BCL-2抑制是靶向过表达OTX2-AS1的髓母细胞瘤细胞的潜在治疗方法。
方法：分析DNA拷贝数改变，甲基化谱，和基因表达数据用于表征髓母细胞瘤组织样品中OTX2-AS1的分子改变。进行髓母细胞瘤细胞模型的体外分析和原位体内实验以表征OTX2-AS1的功能。高通量药物筛选用于确定药物抑制剂，同时进行蛋白质组学和代谢组学分析以探讨药物作用的潜在机制。
结果：我们在一组髓母细胞瘤中检测到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敲除在D283原位髓母细胞瘤小鼠异种移植模型中降低髓母细胞瘤细胞活力和细胞迁移并延长存活。BCL-2的药理学抑制抑制了体外过表达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发生作用，并确定BCL-2抑制是靶向过表达OTX2-AS1的髓母细胞瘤细胞的潜在治疗方法。
