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lnc-HLX-2-7、HLX 和 MYC 之间治疗靶点阳性反馈环促进 3 组髓母细胞瘤。

A therapeutically targetable positive feedback loop between lnc-HLX-2-7, HLX, and MYC that promotes group 3 medulloblastoma.

机构信息

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21231, USA; Johns Hopkins All Children's Hospital, 600 5th St. South, St. Petersburg, FL 33701, USA.

Department of Medical and Molecular Sciences, University of Delaware, 15 Innovation Way, Newark, DE 19701, USA.

出版信息

Cell Rep. 2024 Mar 26;43(3):113938. doi: 10.1016/j.celrep.2024.113938. Epub 2024 Mar 8.

DOI:10.1016/j.celrep.2024.113938
PMID:38460130
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11372658/
Abstract

Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma (MB) formation and progression. We have identified an lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) MBs. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, a sense-overlapping gene of lnc-HLX-2-7, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium-oxide-nanoparticle-coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40%-50% in an intracranial MB xenograft mouse model. Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy. Thus, the lnc-HLX-2-7-HLX-MYC axis is important for regulating G3 MB progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs.

摘要

最近的研究表明，长非编码 RNA（lncRNA）有助于成神经管细胞瘤（MB）的形成和进展。我们已经确定了一个 lncRNA，lnc-HLX-2-7，作为 3 组（G3）MB 的潜在治疗靶点。lnc-HLX-2-7 RNA 特异性地在 HLX 的启动子区域积累，HLX 是 lnc-HLX-2-7 的一个有意义的重叠基因，通过招募包括增强子元件在内的多种因子来激活 HLX 的表达。RNA 测序和染色质免疫沉淀揭示 HLX 结合并激活几个癌基因的启动子，包括 TBX2、LIN9、HOXM1 和 MYC。针对 lnc-HLX-2-7 的铈氧化物纳米颗粒涂层反义寡核苷酸（CNP-lnc-HLX-2-7）的静脉治疗在颅内 MB 异种移植小鼠模型中抑制肿瘤生长 40%-50%。与 CNP-lnc-HLX-2-7 单药治疗相比，CNP-lnc-HLX-2-7 与标准护理顺铂联合使用进一步抑制肿瘤生长并显著延长小鼠存活时间。因此，lnc-HLX-2-7-HLX-MYC 轴对于调节 G3 MB 进展很重要，为将 lnc-HLX-2-7 用作 G3 MB 的治疗靶点提供了强有力的理由。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a52/11372658/d84469fa5bd2/nihms-2004875-f0008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a52/11372658/d84469fa5bd2/nihms-2004875-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a52/11372658/504376733491/nihms-2004875-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a52/11372658/be466c5bf606/nihms-2004875-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a52/11372658/8e9d00b74345/nihms-2004875-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a52/11372658/b419add1ddfc/nihms-2004875-f0005.jpg
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