抑制线粒体内膜蛋白（IMMT）通过线粒体重塑和代谢调节抑制乳腺癌症细胞增殖-动脉网

Suppressing mitochondrial inner membrane protein (IMMT) inhibits the proliferation of breast cancer cells through mitochondrial remodeling and metabolic regulation

Nature 等信源发布 2024-06-04 15:20

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AbstractMetabolic reprogramming is widely recognized as a hallmark of malignant tumors, and the targeting of metabolism has emerged as an appealing approach for cancer treatment. Mitochondria, as pivotal organelles, play a crucial role in the metabolic regulation of tumor cells, and their morphological and functional alterations are intricately linked to the biological characteristics of tumors.

摘要代谢重编程被广泛认为是恶性肿瘤的标志，代谢靶向已成为癌症治疗的一种有吸引力的方法。线粒体作为关键的细胞器，在肿瘤细胞的代谢调节中起着至关重要的作用，其形态和功能改变与肿瘤的生物学特性密切相关。

As a key regulatory subunit of mitochondria, mitochondrial inner membrane protein (IMMT), plays a vital role in degenerative diseases, but its role in tumor is almost unknown. The objective of this research was to investigate the roles that IMMT play in the development and progression of breast cancer (BC), as well as to elucidate the underlying biological mechanisms that drive these effects.

线粒体内膜蛋白（IMMT）作为线粒体的关键调节亚基，在退行性疾病中起着至关重要的作用，但其在肿瘤中的作用几乎未知。这项研究的目的是调查IMMT在乳腺癌（BC）发展和进展中的作用，并阐明驱动这些作用的潜在生物学机制。

In this study, it was confirmed that the expression of IMMT in BC tissues was significantly higher than that in normal tissues. The analysis of The Cancer Genome Atlas (TCGA) database revealed that IMMT can serve as an independent prognostic factor for BC patients. Additionally, verification in clinical specimens of BC demonstrated a positive association between high IMMT expression and larger tumor size (> 2 cm), Ki-67 expression (> 15%), and HER-2 status.

在这项研究中，证实了IMMT在BC组织中的表达显着高于正常组织。对癌症基因组图谱（TCGA）数据库的分析表明，IMMT可以作为BC患者的独立预后因素。此外，在BC临床标本中的验证表明，高IMMT表达与较大的肿瘤大小（>2 cm），Ki-67表达（>15%）和HER-2状态之间呈正相关。

Furthermore, in vitro experiments have substantiated that the suppression of IMMT expression resulted in a reduction in cell proliferation and alterations in mitochondrial cristae, concomitant with the liberation of cytochrome c, but it did not elicit mitochondrial apoptosis. Through Gene Set Enrichment Analysis (GSEA) analysis, we have predicted the associated metabolic genes and discovered that IMMT potentially modulates the advancement of BC through its interaction with 16 metabolic-related genes, and the changes in glycolysis related.

此外，体外实验已经证实，抑制IMMT表达导致细胞增殖减少和线粒体嵴改变，伴随着细胞色素c的释放，但它不会引起线粒体凋亡。通过基因集富集分析（GSEA）分析，我们预测了相关的代谢基因，并发现IMMT可能通过与16个代谢相关基因的相互作用以及糖酵解相关的变化来调节BC的进展。

IntroductionIn terms of malignancies in women, breast cancer (BC) is the most common and one of the leading causes of cancer death worldwide1. The mortality of BC patients has been significantly reduced by radical surgery, radiotherapy, chemotherapy, endocrine therapy, and targeted therapy within the past decade, but many patients still experience recurrence or metastasis, eventually leading to death2.

引言就女性恶性肿瘤而言，乳腺癌（BC）是全球最常见的癌症死亡原因之一1。在过去的十年中，根治性手术，放疗，化疗，内分泌治疗和靶向治疗显着降低了BC患者的死亡率，但许多患者仍会复发或转移，最终导致死亡2。

The utilization of molecular typing, specifically with regards to the estrogen and progesterone receptors (ER and PR), human epidermal growth factor receptor 2 (HER-2), and other markers, has significantly enhanced the precision of treatment for BC. However, the biological diversity of this disease presents a formidable obstacle in the development of personalized therapies3.Metabolic reprogramming is regarded as a hallmark of malignant neoplasms, and a large number of investigations have demonstrated that the metabolic traits and predilections of tumors undergo alterations throughout the course of cancer development4.

分子分型的利用，特别是关于雌激素和孕激素受体（ER和PR），人表皮生长因子受体2（HER-2）和其他标记物的利用，显着提高了BC治疗的精确度。然而，这种疾病的生物多样性给个性化治疗的发展带来了巨大的障碍。代谢重编程被认为是恶性肿瘤的标志，大量研究表明，肿瘤的代谢特征和偏好在整个癌症发展过程中都会发生改变4。

At the early stage, tumor growth requires a large amount of nutrient absorption and biosynthesis, and additional subtype-selective metabolic requirements arise during infiltration, which rely on new pathways for growth and metastasis5. Mitochondria are the key organelles involved in metabolic reprogramming in tumor cells, and maintaining mitochondrial integrity is the absolute basis of oxidative phosphorylation6.

在早期阶段，肿瘤生长需要大量的营养吸收和生物合成，并且在浸润过程中会产生额外的亚型选择性代谢需求，这依赖于新的生长和转移途径5。线粒体是参与肿瘤细胞代谢重编程的关键细胞器，维持线粒体完整性是氧化磷酸化的绝对基础6。

In addition, previous studies have also indicated that the number, structure, and function of mitochondria often change in malignant tumor cells to meet the needs of rapid growth in acidic and anoxic environments7.As a key regulatory subunit of mitochondrial integrity, mitochondrial inner membrane protein (IMMT), also known as Mic-60 or Mitofilin8, .

此外，先前的研究还表明，恶性肿瘤细胞中线粒体的数量，结构和功能经常发生变化，以满足在酸性和缺氧环境中快速生长的需要7。作为线粒体完整性的关键调节亚基，线粒体内膜蛋白（IMMT），也称为Mic-60或Mitofilin8。

Data availability

数据可用性

Public data were shared and available on the following websites: TCGA (http://cancergenome.nih.gov/), The K-M Plotter Tool (http://kmplot.com/analysis/), HPA online tool (http://www.proteatlas.org), GEPIA (https://GEPIA.cancer-PKU.cn/) and TIMER2.0 (http://timer.cistrome.org/). Most of the results of the current study appear in the article or as supplementary materials.

公共数据已在以下网站上共享和提供：TCGA(http://cancergenome.nih.gov/)，K-M绘图仪工具(http://kmplot.com/analysis/)，HPA在线工具(http://www.proteatlas.org)，格皮亚(https://GEPIA.cancer-PKU.cn/)和定时器2.0(http://timer.cistrome.org/)。当前研究的大多数结果都出现在文章中或作为补充材料。

In case of reasonable request, the corresponding author can provide further details regarding the data. Generated Statement: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation..

如果有合理的要求，通讯作者可以提供有关数据的更多详细信息。生成的声明：支持本文结论的原始数据将由作者提供，无需过度保留。。

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McGranahan，N。＆Swanton，C。克隆异质性和肿瘤进化：过去，现在和未来。细胞168（4），613-628（2017）。文章

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Bhattacharya, B., Mohd, O. M. & Soong, R. The Warburg effect and drug resistance. Br. J. Pharmacol. 173(6), 970–979 (2016).Article

Bhattacharya，B.，Mohd，O.M。和Soong，R。Warburg效应和耐药性。Br.J.药理学。173（6），970-979（2016）。文章

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Download referencesFundingThis study was funded by National Natural Science Foundation of China (NSFC 82160484, NSFC 81960494 and NSFC 82002824) and Guizhou Province Science Plan Program (Qian Ke He Foundation ZK [2022] General 640).Author informationAuthor notesThese authors contributed equally: Li Liu and Qingqing Zhao.Authors and AffiliationsClinical Medical College, Zunyi Medical University, Zunyi, ChinaLi Liu, Qingqing Zhao & Dan LiDepartment of Laboratory Medicine, Affiliated Hospital of ZunYi Medical University, Zunyi, ChinaJie Du, Yunfei Huang & Yan YangSchool of Laboratory Medicine, Zunyi Medical University, Zunyi, ChinaJie Du, Yunfei Huang & Yan YangDepartment of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, ChinaDaigang Xiong & Rui ChenDepartment of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, ChinaDaigang Xiong & Rui ChenAuthorsLi LiuView author publicationsYou can also search for this author in.

下载参考文献资助本研究由国家自然科学基金（NSFC 82160484，NSFC 81960494和NSFC 82002824）和贵州省科学计划项目（钱克河基金ZK[2022]General 640）资助。作者信息作者注意到这些作者做出了同样的贡献：Li Liu和Qingqing Zhao。作者和附属机构遵义医科大学临床医学院，遵义，中国Liu，赵清清和Dan Lide遵义医科大学附属医院检验医学系，遵义，中国Jie Du，黄云飞和Yan Yang遵义医科大学检验医学院，遵义，中国Jie Du，黄云飞和Yan Yang遵义医科大学附属医院普外科，遵义，中国戴刚熊和陈锐遵义医科大学附属医院甲状腺和乳腺外科，中国戴刚熊和陈锐作者Liu Liu View作者出版物您也可以搜索作者在。

PubMed Google ScholarQingqing ZhaoView author publicationsYou can also search for this author in

PubMed谷歌学者赵清清查看作者出版物您也可以在

PubMed Google ScholarDaigang XiongView author publicationsYou can also search for this author in

PubMed Google ScholarDaigang XiongView作者出版物您也可以在

PubMed Google ScholarDan LiView author publicationsYou can also search for this author in

PubMed Google ScholarDan LiView作者出版物您也可以在

PubMed Google ScholarJie DuView author publicationsYou can also search for this author in

PubMed Google ScholarJie DuView作者出版物您也可以在

PubMed Google ScholarYunfei HuangView author publicationsYou can also search for this author in

PubMed Google ScholarYunfei Huang查看作者出版物您也可以在

PubMed Google ScholarYan YangView author publicationsYou can also search for this author in

PubMed Google ScholarYan YangView作者出版物您也可以在

PubMed Google ScholarRui ChenView author publicationsYou can also search for this author in

PubMed Google ScholarRui ChenView作者出版物您也可以在

PubMed Google ScholarContributionsConception and design: RC, YY, LL and QQZ. Bioinformatics Analysis: LL, DL and RC. Clinical data collection: QQZ and LL. Cell experiments and immunohistochemistry: LL, YFH, and JD. Data analysis and interpretation: LD, LL, JD, DGX and YY. Manuscript writing: QQZ, LL and RC.

PubMed谷歌学术贡献概念和设计：RC，YY，LL和QQZ。生物信息学分析：LL，DL和RC。临床数据收集：QQZ和LL。细胞实验和免疫组织化学：LL，YFH和JD。数据分析和解释：LD，LL，JD，DGX和YY。手稿撰写：QQZ，LL和RC。

Manuscript review and modification: RC and YY. In addition to contributing to the manuscript, all authors approved the version submitted.Corresponding authorsCorrespondence to.

稿件审查和修改：RC和YY。除了对手稿做出贡献外，所有作者都批准了提交的版本。通讯作者通讯。

Yan Yang or Rui Chen.Ethics declarations

Yan Yang或Rui Chen。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Additional informationPublisher's noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary InformationSupplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Table S1.Supplementary Table S2.Supplementary Table S3.Supplementary Table S4.Rights and permissions.

Additional informationPublisher的noteSpringer Nature在已发布地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充信息1。补充信息2。补充信息3。补充表S1。补充表S2。补充表S3。补充表S4。权限。

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

开放获取本文是根据知识共享署名4.0国际许可证授权的，该许可证允许以任何媒体或格式使用，共享，改编，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出是否进行了更改。

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Reprints and permissionsAbout this articleCite this articleLiu, L., Zhao, Q., Xiong, D. et al. Suppressing mitochondrial inner membrane protein (IMMT) inhibits the proliferation of breast cancer cells through mitochondrial remodeling and metabolic regulation.

转载和许可本文引用本文Liu，L.，Zhao，Q.，Xiong，D。等人。抑制线粒体内膜蛋白（IMMT）通过线粒体重塑和代谢调节抑制乳腺癌细胞的增殖。

Sci Rep 14, 12766 (2024). https://doi.org/10.1038/s41598-024-63427-8Download citationReceived: 28 February 2024Accepted: 29 May 2024Published: 04 June 2024DOI: https://doi.org/10.1038/s41598-024-63427-8Share 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.

科学报告1412766（2024）。https://doi.org/10.1038/s41598-024-63427-8Download引文接收日期：2024年2月28日接受日期：2024年5月29日发布日期：2024年6月4日OI：https://doi.org/10.1038/s41598-024-63427-8Share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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KeywordsMitochondrial inner membrane protein (IMMT)Breast cancerMitochondria remodelingMetabolic reprogrammingPrognostic marker

关键词线粒体内膜蛋白（IMMT）乳腺癌线粒体重塑代谢重编程预后标志物

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