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: 10518721
• 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/10518721
• 关键词: 3-Dimensional; Address; Affect; Antisense Oligonucleotides; Apoptosis; 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; Foundations; Gene Expression Profile; Genes; Genetic; H2 gene; Hematopoietic Neoplasms; Homeobox; Homeobox Genes; Human; Immunocompromised Host; Individual; 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; Signaling Protein; Subgroup; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Side Effects; Untranslated RNA; Up-Regulation; Work; aggressive therapy; cancer type; cerium oxide nanoparticle; experimental study; 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.

项目总结