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

项目摘要 脑瘤在儿童中相对常见，其中髓母细胞瘤(MB)最常见 打字，尤其是五岁以下的儿童。MBS可以通过脑脊液传播，并且 在诊断时，转移是常见的。一些调控基因，信号 MB中的通路和基因调控网络是已知的，但非编码RNA在MB中的作用 MB，特别是长的非编码RNA(LncRNAs)，描述得很差。通过施加机 学习公开可用的rna-seq数据集，我们发现lnc-hlx2-7高度上调。 对于难治性和预后不良的3级(G3)MBS与其他 分子亚群。CRISPR-Cas9对G3MB细胞中lnc-HLX-2-7基因的耗竭作用 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G3MB细胞注射到小鼠小脑中，它们产生了 比来自亲代细胞的肿瘤小得多。此外，氧化铈 纳米包被反义寡核苷酸对体内肿瘤抑制作用的研究 成长。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)的调节子 磷酸核糖基转移酶(NAMPT)，调节NAD+产生的关键酶。以上内容 结果突出了lnc-HLX-2-7对G3MB发育的功能影响，一些 潜在的作用机制，以及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 MBS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G3MBS的临床前治疗；(B)描述由lnc-hlx-2-7驱动的分子 G3MB肿瘤的潜在机制，以及(C)确定lnc-HLX-2-7是如何调节和 调节G3MBS中的其他基因。这项研究将提供有价值的机制洞察如何 LNC-HLX-2-7推动G3 MB的发展，推进临床前治疗靶向 挑战亚群，并预期补偿和抵抗机制。本研究 对lncRNAs如何在大脑和其他组织中作为关键癌基因发挥作用提供了重要的见解 癌症。

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.