Cell Death & Disease：由circCOPA编码的一种新蛋白抑制胶质母细胞瘤细胞的恶性表型，并通过破坏NONO-SFPQ复合物增加其对替莫唑胺的敏感性-动脉网

Cell Death & Disease：A novel protein encoded by circCOPA inhibits the malignant phenotype of glioblastoma cells and increases their sensitivity to temozolomide by disrupting the NONO–SFPQ complex

Nature 等信源发布 2024-08-25 15:45

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AbstractGlioblastoma (GBM) represents a primary malignant brain tumor. Temozolomide resistance is a major hurdle in GBM treatment. Proteins encoded by circular RNAs (circRNAs) can modulate the sensitivity of multiple tumor chemotherapies. However, the impact of circRNA-encoded proteins on GBM sensitivity to temozolomide remains unknown.

摘要胶质母细胞瘤（GBM）是一种原发性恶性脑肿瘤。替莫唑胺耐药是GBM治疗的主要障碍。由环状RNA（circRNA）编码的蛋白质可以调节多种肿瘤化学疗法的敏感性。然而，circRNA编码的蛋白质对GBM对替莫唑胺敏感性的影响仍然未知。

Herein, we discover a circRNA (circCOPA) through the circRNA microarray profile in GBM samples, which can encode a novel 99 amino acid protein (COPA-99aa) through its internal ribosome entry site. Functionally, circCOPA overexpression in GBM cells inhibits cell proliferation, migration, and invasion in vitro and growth in vivo.

在此，我们通过GBM样品中的circRNA微阵列谱发现了circRNA（circCOPA），它可以通过其内部核糖体进入位点编码新的99个氨基酸的蛋白质（COPA-99aa）。在功能上，GBM细胞中的circCOPA过表达抑制体外细胞增殖，迁移和侵袭以及体内生长。

Rather than itself, circCOPA mainly functions as a suppressive effector by encoding COPA-99aa. Moreover, we reveal that circCOPA is downregulated in GBM tissues and high expression of circCOPA is related to a better prognosis in GBM patients. Mechanistically, a heteromer of SFPQ and NONO is required for double-strand DNA break repair.

circCOPA主要通过编码COPA-99aa而不是其本身起抑制效应子的作用。此外，我们发现circCOPA在GBM组织中下调，circCOPA的高表达与GBM患者更好的预后有关。从机理上讲，双链DNA断裂修复需要SFPQ和NONO的异聚体。

COPA-99aa disrupts the dimerization of NONO and SFPQ by separately binding with the NONO and SFPQ proteins, thus resulting in the inhibition of proliferation or invasion and the increase of temozolomide-induced DNA damage in GBM cells. Collectively, our data suggest that circCOPA mainly contributes to inhibiting the GBM malignant phenotype through its encoded COPA-99aa and that COPA-99aa increases temozolomide-induced DNA damage by interfering with the dimerization of NONO and SFPQ.

COPA-99aa通过分别与NONO和SFPQ蛋白结合来破坏NONO和SFPQ的二聚化，从而导致GBM细胞增殖或侵袭的抑制以及替莫唑胺诱导的DNA损伤的增加。总的来说，我们的数据表明，circCOPA主要通过其编码的COPA-99aa来抑制GBM恶性表型，而COPA-99aa通过干扰NONO和SFPQ的二聚化来增加替莫唑胺诱导的DNA损伤。

Restoring circCOPA or COPA-99aa may increase the sensitivity of patients to temozolomide..

恢复circCOPA或COPA-99aa可能会增加患者对替莫唑胺的敏感性。。

IntroductionGBM ranks as the most prevalent form of primary malignant brain tumor [1], accounting for approximately 75% of all malignant tumors of the central nervous system [2]. Currently, the treatment of GBM primarily involves surgery combined with radiotherapy, temozolomide (TMZ) chemotherapy, immunotherapy and tumor-treating fields (TTFields) [3,4,5].

引言GBM是原发性恶性脑肿瘤最常见的形式，约占中枢神经系统所有恶性肿瘤的75%[2]。目前，GBM的治疗主要包括手术联合放疗，替莫唑胺（TMZ）化疗，免疫治疗和肿瘤治疗领域（TTFields）[3,4,5]。

Unfortunately, patients with GBM have a dismal prognosis.Circular RNAs (circRNAs) are a class of single-stranded noncoding RNAs with covalent closed-loop structures [6]. They are considered as diagnostic markers and therapeutic targets for many types of tumors, including GBM [7, 8]. An increasing number of studies have shown that aberrantly expressed circRNAs play important roles in the occurrence and progression of GBM [7].

不幸的是，GBM患者预后不佳。环状RNA（circRNA）是一类具有共价闭环结构的单链非编码RNA。它们被认为是许多类型肿瘤的诊断标志物和治疗靶点，包括GBM[7，8]。越来越多的研究表明，异常表达的circRNA在GBM的发生和发展中起着重要作用。

For instance, circRNAs can disrupt glycolysis and promote the MDA5-mediated immune response by binding with TKFC proteins, thus suppressing the progression of glioma [9]. By functioning as miRNA sponges, circRNAs can promote glioma tumorigenesis [10]. Importantly, through internal ribosome entry sites (IRESs), N6-methyladenosine modifications or infinite open reading frames, circRNAs can encode unique peptides/proteins.

例如，circRNA可以通过与TKFC蛋白结合来破坏糖酵解并促进MDA5介导的免疫应答，从而抑制胶质瘤的进展。通过作为miRNA海绵的功能，circRNA可以促进神经胶质瘤的肿瘤发生。重要的是，通过内部核糖体进入位点（IREs），N6-甲基腺苷修饰或无限开放阅读框，circRNA可以编码独特的肽/蛋白质。

The impact of circRNA-encoded proteins/peptides on the malignant phenotype of GBM has received widespread attention [11, 12]. CircRNAs are increasingly recognized as potential targets for the treatment of various diseases, including GBM [13,14,15].TMZ presents the primary chemotherapy drug for GBM treatment and causes cytotoxicity by causing DNA double-strand break (DSB) [16].

circRNA编码的蛋白质/肽对GBM恶性表型的影响受到了广泛关注[11，12]。circRNA越来越被认为是治疗各种疾病的潜在靶点，包括GBM[13，14，15]。TMZ是GBM治疗的主要化疗药物，通过引起DNA双链断裂（DSB）引起细胞毒性。

The response of DNA damage repair can reverse the damage and lead to TMZ chemotherapeutic resistance [17]. Many studies have reported that the NONO–SFPQ complex is a heterodimer [18, 19] and is involved in DN.

DNA损伤修复的反应可以逆转损伤并导致TMZ化疗耐药（17）。许多研究报道，NONO-SFPQ复合物是异二聚体[18，19]，与DN有关。

Data availability

数据可用性

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

本研究中使用和/或分析的数据集可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsWe would like to thank American Journal Experts (AJE) for the paper revision support.FundingThe project was supported by grants (Nos. 81773187, 82273493) from National Natural Science Foundation of China. The project was sponsored by Tianjin Health Research Project (TJWJ2023ZD001) and the Natural Science Foundation of Henan Province for Excellent Young Scholars (No.

下载参考文献致谢我们要感谢美国期刊专家（AJE）对论文修订的支持。资助该项目得到了国家自然科学基金资助（编号8177318782273493）。该项目由天津市健康研究项目（TJWJ2023ZD001）和河南省优秀青年自然科学基金（No。

232300421057).Author informationAuthor notesThese authors contributed equally: Dazhao Peng, Cheng Wei, Boyuan Jing.Authors and AffiliationsTianjin Neurological Institute, Key Laboratory of Post-Neuro injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, ChinaDazhao Peng, Cheng Wei, Boyuan Jing, Runze Yu & Lei HanDepartment of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaZhenyu ZhangAuthorsDazhao PengView author publicationsYou can also search for this author in.

232300421057）。作者信息作者注意到这些作者做出了同样的贡献：彭大钊，程伟，景伯元。作者和附属机构天津神经病学研究所，教育部和天津市中枢神经系统后神经损伤，神经修复和再生重点实验室，天津医科大学总医院，天津，中国天津彭大钊，程伟，景伯元，余润泽和雷手郑州大学第一附属医院神经外科，河南郑州，张振宇作者彭大钊作者出版物您也可以在中搜索作者。

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PubMed Google ScholarContributionsDP, CW, and BJ contributed equally to this study and made substantial contributions to conception and design, performing experiments, acquisition of data, and interpretation of data. RY was mainly responsible for drafting the article and editing the data.

PubMed谷歌学术贡献SDP，CW和BJ对这项研究做出了同样的贡献，并为概念和设计，进行实验，获取数据和解释数据做出了重大贡献。RY主要负责起草文章和编辑数据。

LH and ZZ had given final approval of the version to be published. All authors read and approved the final manuscript.Corresponding authorsCorrespondence to.

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Ethics approval and consent to participate

道德批准和同意参与

This study was approved by the Human Scientific Ethics Committee of the First Affiliated Hospital of Zhengzhou University, and written informed consent was obtained from all patients.

本研究经郑州大学第一附属医院人类科学伦理委员会批准，并获得所有患者的书面知情同意书。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by Giovanni BlandinoSupplementary informationSupplementary materialsSupplementary Table 1Supplementary Table 2Original western blotsRights and permissions.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。由Giovanni Blandinos编辑补充信息补充材料补充表1补充表2原始蛋白质印迹权利和权限。

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Reprints and permissionsAbout this articleCite this articlePeng, D., Wei, C., Jing, B. et al. A novel protein encoded by circCOPA inhibits the malignant phenotype of glioblastoma cells and increases their sensitivity to temozolomide by disrupting the NONO–SFPQ complex.

转载和许可本文引用本文Peng，D.，Wei，C.，Jing，B。等人。由circCOPA编码的新型蛋白质通过破坏NONO-SFPQ复合物抑制胶质母细胞瘤细胞的恶性表型并增加其对替莫唑胺的敏感性。

Cell Death Dis 15, 616 (2024). https://doi.org/10.1038/s41419-024-07010-zDownload citationReceived: 24 April 2024Revised: 10 August 2024Accepted: 16 August 2024Published: 25 August 2024DOI: https://doi.org/10.1038/s41419-024-07010-zShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

细胞死亡Dis 15616（2024）。https://doi.org/10.1038/s41419-024-07010-zDownload引文收到日期：2024年4月24日修订日期：2024年8月10日接受日期：2024年8月16日发布日期：2024年8月25日OI：https://doi.org/10.1038/s41419-024-07010-zShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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