Regulation, function, and the therapeutic potential of an oncogenic long noncoding RNA lnc-HLX-2-7 in group 3 medulloblastomas

致癌长链非编码 RNA lnc-HLX-2-7 在第 3 组髓母细胞瘤中的调节、功能和治疗潜力

• 批准号: 10661070
• 负责人: Ranjan Joseph Perera
• 金额: $ 41.76万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661070
• 关键词: 3-Dimensional; Address; Affect; Antisense Oligonucleotides; Binding Proteins; Brain; Brain Neoplasms; CRISPR/Cas technology; Cell Proliferation; Cell physiology; Cells; Central Nervous System Neoplasms; Cerebellum; Cerebrospinal Fluid; Child; Cisplatin; Citric Acid Cycle; Clinical; Clinical Treatment; Data; Data Set; Development; Diagnosis; Disease; Enzymes; Epigenetic Process; Experimental Models; Foundations; Gene Expression Profile; Genes; Genetic; H2 gene; Hematopoietic Neoplasms; Homeobox; Human; Immunocompromised Host; Individual; Induction of Apoptosis; Invaded; Machine Learning; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Nicotinamide adenine dinucleotide; Oligonucleotides; Oncogenes; Oncogenic; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Pre-Clinical Model; Preclinical Testing; Primary Neoplasm; Production; Prognosis; RNA-Binding Proteins; Recurrence; Regulation; Regulator Genes; Regulatory Element; Resistance; Role; Safety; Secondary to; Signal Pathway; Subgroup; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Side Effects; Untranslated RNA; Up-Regulation; Work; aggressive therapy; cancer type; cerium oxide nanoparticle; gene regulatory network; genetic signature; genomic locus; human disease; human model; in vivo; inhibitor; innovation; insight; lead candidate; medulloblastoma; molecular targeted therapies; mortality; mouse model; nanoparticle; nicotinamide phosphoribosyltransferase; novel; overexpression; particle; pre-clinical; resistance mechanism; response; spatiotemporal; targeted agent; therapeutic evaluation; therapeutic target; therapeutically effective; transcription factor; transcriptome sequencing; treatment response; tumor; tumor growth; tumor metabolism; tumor progression

Project Summary Brain tumors are relatively common in children, with medulloblastoma (MB) the most frequent type, especially in children under five. MBs can spread through the cerebrospinal fluid, and metastases are common at the time of diagnosis. Some of the regulatory genes, signaling pathways, and gene regulatory networks in MB are known, but the role of non-coding RNAs in MB, particularly long non-coding RNAs (lncRNAs), are poorly described. By applying machine learning to publicly available RNA-seq datasets, we found that lnc-HLX2-7 was highly upregulated and specific for difficult-to-treat and poor prognosis grade 3 (G3) MBs compared with other molecular subgroups. CRISPR-Cas9 depletion of lnc-HLX-2-7 in G3 MB cells significantly reduced cell proliferation, invasion, and 3D colony formation and induced apoptosis. When lnc- HLX-2-7-deleted G3 MB cells were injected into the mouse cerebellum, they produced considerably smaller tumors than those derived from parental cells. Further, cerium oxide nanoparticle-coated antisense oligonucleotides (ASOs) against lnc-HLX2-7 reduced in vivo tumor growth. Our preliminary results also demonstrate that lnc-HLX-2-7 is a critical MB metabolic regulator that modulates NAD+ (nicotinamide adenine dinucleotide) via nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme mediating NAD+ production. The above results highlight the functional impact of lnc-HLX-2-7 on G3 MB development, some of the underlying mechanisms of action, and its importance as a therapeutic target. Our central hypothesis is that lnc-HLX-2-7 is an important oncogenic molecule that can be therapeutically targeted in G3 MBs. We propose the following three Specific Aims to test our hypothesis: (a) to test pre-clinical therapeutics targeting G3 MBs; (b) to delineate the lnc-HLX-2-7-driven molecular mechanisms underlying G3 MB tumors, and (c) to identify how lnc-HLX-2-7 is regulated and regulates other genes in G3 MBs. This study will provide valuable mechanistic insights into how lnc-HLX-2-7 drives G3 MB development, advance pre-clinical therapeutic targeting of this challenging subgroup, and anticipate compensatory and resistance mechanisms. This study provides important insights into how lncRNAs function as critical oncogenes in the brain and other cancers.

项目概要 脑肿瘤在儿童中相对常见，其中髓母细胞瘤 (MB) 最常见 型，特别是五岁以下的儿童。 MB 可以通过脑脊液传播，并且 诊断时转移很常见。一些调控基因、信号传导 MB 中的途径和基因调控网络是已知的，但非编码 RNA 在 MB 中的作用 MB，特别是长非编码 RNA (lncRNA) 的描述很少。通过应用机 通过学习公开的 RNA-seq 数据集，我们发现 lnc-HLX2-7 高度上调 与其他药物相比，针对难以治疗和预后不良的 3 级 (G3) MB 分子亚群。 CRISPR-Cas9 显着耗尽 G3 MB 细胞中的 lnc-HLX-2-7 减少细胞增殖、侵袭和 3D 集落​​形成并诱导细胞凋亡。当lnc- 将 HLX-2-7 缺失的 G3 MB 细胞注射到小鼠小脑中，它们产生 与源自亲本细胞的肿瘤相比，肿瘤小得多。 [0012] 进一步地，氧化铈 纳米颗粒包被的反义寡核苷酸 (ASO) 对抗 lnc-HLX2-7 减少体内肿瘤 生长。我们的初步结果还表明，lnc-HLX-2-7 是一种关键的 MB 代谢 通过烟酰胺调节 NAD+（烟酰胺腺嘌呤二核苷酸）的调节剂 磷酸核糖基转移酶 (NAMPT)，一种介导 NAD+ 产生的关键酶。以上 结果强调了 lnc-HLX-2-7 对 G3 MB 发育的功能影响，一些 潜在的作用机制及其作为治疗靶点的重要性。我们的中央 假设 lnc-HLX-2-7 是一种重要的致癌分子，可用于治疗 以 G3 MB 为目标。我们提出以下三个具体目标来检验我们的假设：(a) 测试针对 G3 MB 的临床前疗法； (b) 描绘lnc-HLX-2-7驱动的分子 G3 MB 肿瘤的潜在机制，以及 (c) 确定 lnc-HLX-2-7 的调控方式和 调节 G3 MB 中的其他基因。这项研究将为我们提供有价值的机制见解 lnc-HLX-2-7 推动 G3 MB 开发，推进该药物的临床前治疗靶向 具有挑战性的亚组，并预测补偿和抵抗机制。这项研究 提供了关于 lncRNA 如何作为大脑和其他部位的关键癌基因发挥作用的重要见解 癌症。