一种新的Nav1.5依赖性反馈机制驱动癌症转移糖酵解酸化-动脉网

A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis

Nature 等信源发布 2024-07-25 09:02

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AbstractSolid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood.

摘要实体瘤具有反常的高细胞内[Na2+]。的细胞内[Na2+]。的细胞内[Na2+]。的细胞内]含量。的细胞内[Na2+]含量。的细胞内[Na2+]含量高。的细胞内[Na2+]含量。各种Na+通道的活性可能是这种Na+积累的基础。电压门控Na+通道（VGSC）已被证明在癌细胞系中具有功能活性，在癌细胞系中它们促进侵袭。然而，所涉及的机制和临床相关性尚不完全清楚。

Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts.

在这里，我们显示Nav1.5 VGSC亚型的蛋白质表达与乳腺癌患者的转移增加和癌症特异性生存期缩短密切相关。此外，VGSC在患者来源的乳腺肿瘤细胞，细胞系和癌症相关成纤维细胞中具有功能活性。

Knockdown of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis.

在乳腺癌小鼠模型中敲低Nav1.5抑制侵袭调节基因的表达。Nav1.5活性可能通过上调Na+/K+ATP酶的活性来增加乳腺癌细胞中的ATP需求和糖酵解，从而促进H+产生和细胞外酸化。。

In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment..

反过来，酸性细胞外pH升高了Na+通过Nav1.5持续流入乳腺癌细胞。总之，这些发现显示细胞外酸化与Na+进入癌细胞之间的正反馈，这可以促进侵袭。这些结果突出了Nav1.5活性作为乳腺癌转移增强剂的临床意义，并为VGSC抑制剂在癌症治疗中的应用提供了进一步的证据。。

IntroductionBreast cancer is the leading cause of cancer-related deaths in women worldwide [1] and most deaths are due to metastatic disease resulting from poor treatment options and therapy resistance [2]. Around 20–30% of patients with primary breast cancer will go on to develop distant metastasis and once this has been diagnosed, there is currently no cure available.

。大约20-30%的原发性乳腺癌患者将继续发展为远处转移，一旦确诊，目前尚无治愈方法。

Thus, there is an urgent need for improved treatments to prevent or reduce breast cancer metastasis.Increasing evidence points to ion channels as key regulators of cancer progression [3,4,5,6]. Members of the voltage-gated Na+ channel (VGSC) family are upregulated in multiple cancer types [7]. In solid cancers, including breast, prostate, lung, and colon cancer, VGSC activity promotes cellular invasion [8, 9].

因此，迫切需要改进治疗方法以预防或减少乳腺癌转移。越来越多的证据表明离子通道是癌症进展的关键调节因子[3,4,5,6]。电压门控Na+通道（VGSC）家族的成员在多种癌症类型中上调（7）。在包括乳腺癌，前列腺癌，肺癌和结肠癌在内的实体癌中，VGSC活性促进细胞侵袭[8，9]。

In breast cancer, the Nav1.5 subtype is upregulated at the mRNA level compared to normal tissue and is associated with recurrence and metastasis [10]. Nav1.5 is also upregulated in breast cancers at the protein level [11, 12], predominantly in its neonatal D1:S3 splice form [13]; however, the sample sizes of these studies were too small to reliably determine the relationship between Nav1.5 expression and clinical outcome.

在乳腺癌中，与正常组织相比，Nav1.5亚型在mRNA水平上调，并与复发和转移有关。Nav1.5在乳腺癌中也在蛋白质水平上调[11，12]，主要是在其新生儿D1:S3剪接形式中[13]；然而，这些研究的样本量太小，无法可靠地确定Nav1.5表达与临床结果之间的关系。

Electrophysiological methods have not yet been used to investigate functional Nav1.5 activity in breast cancer tissue or primary cell cultures. Nonetheless, Na+ currents carried by Nav1.5 have been detected in a small number of breast cancer cell lines and in tissue slices from murine tumour xenografts [11, 12, 14, 15].

电生理学方法尚未用于研究乳腺癌组织或原代细胞培养物中的功能性Nav1.5活性。尽管如此，在少数乳腺癌细胞系和小鼠肿瘤异种移植物的组织切片中已经检测到Nav1.5携带的Na+电流[11,12,14,15]。

In these cells, the persistent Na+ current (as distinct from the transient, inactivating Na+ current), which passes through the channels at the resting membrane potential (Vm), has been shown to potentiate cellular invasion in vitro and tumour growth and metastasis.

在这些细胞中，在静息膜电位（Vm）下通过通道的持续Na+电流（不同于瞬时失活的Na+电流）已被证明可增强体外细胞侵袭以及肿瘤生长和转移。

To assess the voltage dependence of activation of VGSCs and K+ channels, cells were held at −120 mV for 250 ms and then depolarised to test potentials in 5–10 mV steps between −120 mV and +30 mV for 50 ms.

为了评估VGSC和K+通道激活的电压依赖性，将细胞保持在-120 mV 250 ms，然后去极化以在-120 mV和+30 mV之间以5-10 mV的步长测试电位50 ms。

To assess the voltage dependence of steady-state inactivation, cells were held at −120 mV for 250 ms followed by prepulses for 250 ms in 5–10 mV steps between −120 mV and +30 mV and a test pulse to −10 mV for 50 ms.

为了评估稳态失活的电压依赖性，将细胞保持在-120 mV 250 ms，然后在-120 mV和+30 mV之间以5-10 mV的步长预脉冲250 ms，并将测试脉冲保持在-10 mV 50 ms。

PharmacologyTetrodotoxin citrate (TTX, HelloBio HB1035) was diluted in sterile-filtered water to a stock concentration of 1 mM TTX/8.44 mM citrate and stored at −30 °C. The working concentration was 30 μM TTX/253 μM citrate. Ouabain octahydrate (Sigma O3125) was diluted in DMSO to a stock concentration of 50 mM and stored at −30 °C.

将药理学柠檬酸曲毒素（TTX，HelloBio HB1035）在无菌过滤水中稀释至1mM TTX/8.44mM柠檬酸盐的储备浓度，并保存在-30℃。工作浓度为30μMTTX/253μM柠檬酸盐。将哇巴因八水合物（Sigma O3125）在DMSO中稀释至50mM的储备浓度，并保存在-30℃。

The working concentration was 300 nM. Cariporide (Santa Cruz Biotechnology SC337619) was diluted in DMSO to a stock concentration of 50 mM and stored at −30 °C. The working concentration was 20 μM. Sodium iodoacetate (Acros Organics 170970250) was diluted in water and made up immediately before each experiment.

。将Cariporide（Santa Cruz Biotechnology SC337619）在DMSO中稀释至50mM的储备浓度，并保存在-30℃。工作浓度为20μM。将碘乙酸钠（Acros Organics 170970250）在水中稀释并在每次实验前立即配制。

The working concentration was 2 μM. Oligomycin (Santa Cruz Biotechnology SC201551) was diluted to a stock concentration of 10 mM in DMSO and stored at −30 °C. The working concentration was 1 μM. 3-Bromopyruvate (Apexbio B7922) was diluted in DMSO and stored at −20 °C. The working concentration range was 250 µM–1 mM.

工作浓度为2μM。将寡霉素（Santa Cruz Biotechnology SC201551）在DMSO中稀释至10 mM的储备浓度，并保存在-30℃。工作浓度为1μM。将3-溴丙酮酸（Apexbio B7922）在DMSO中稀释并保存在-20℃。工作浓度范围为250μM-1mM。

Veratridine was diluted in DMSO to a stock concentration of 50 mM and stored at −20 °C. The working concentration was 100 µM.RNA sequencingMice were housed (up to 4/cage) and were chosen at random for cell implantation ensuring that both cell types were represented within each cage/block. RNA was extracted from 12 xenograft tumours (6 control MDA-MB-231 tumours and 6 Nav1.5 knockdown MDA-MB-231 tumours; blinded to sample type) using TRIzol (Invitrogen), according to the manufacturer’s instructions.

将藜芦碱在DMSO中稀释至50mM的储备浓度，并保存在-20℃。工作浓度为100μM。RNA测序将小鼠圈养（最多4只/笼），并随机选择用于细胞植入，确保两种细胞类型均在每个笼/块内表示。根据制造商的说明，使用TRIzol（Invitrogen）从12个异种移植肿瘤（6个对照MDA-MB-231肿瘤和6个Nav1.5敲低MDA-MB-231肿瘤；不知道样品类型）中提取RNA。

A sample size of 6/group was used for the RNA-seq experiments, in accordance with standard practice/recommendations [74]. RNA quality assessment, library preparation, and 150 bp short-read, paired-end sequencing were conducted by Novogene Europe (Cambridge, UK) with 1 µg of total RNA used for sequencing library construction with.

根据标准实践/建议（74），RNA-seq实验使用6个/组的样本量。Novogene Europe（英国剑桥）进行了RNA质量评估，文库制备和150 bp短读配对末端测序，其中1µg总RNA用于测序文库构建。

Data availability

数据可用性

The RNA-seq data are deposited in the GEO database, accession number GSE228621.

RNA-seq数据保存在GEO数据库中，登录号为GSE228621。

Code availability

代码可用性

The code used to analyse the data is available from https://github.com/andrewholding/RNASeq-SCN5A.

用于分析数据的代码可从https://github.com/andrewholding/RNASeq-SCN5A.

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Download referencesAcknowledgementsThe authors wish to acknowledge the roles of the Breast Cancer Now Tissue Bank in collecting and making available the samples and data, and the patients who have generously donated their tissues and shared their data to be used in the generation of this publication.

下载参考文献致谢作者希望感谢乳腺癌Now组织库在收集和提供样本和数据方面的作用，以及慷慨捐赠组织并分享数据以用于本出版物生成的患者。

The authors also thank Prof. Miles Whittington (Hull-York Medical School, UK), Dr. John Davey and Dr. Katherine Newling (Technology Facility, University of York, UK), and Prof. Lýdia Vargová (Charles University, Czechia) for providing invaluable advice. For the purpose of open access, a Creative Commons Attribution (CC BY) licence is applied to any author accepted manuscript version arising from this submission.FundingWJB received funding from Breast Cancer Now (2015NovPhD572), Cancer Research UK (A25922), and the BBSRC (BB/Y513970/1).

作者还感谢Miles Whittington教授（英国赫尔约克医学院），John Davey博士和Katherine Newling博士（英国约克大学技术设施）以及Lýdia Vargová教授（捷克查尔斯大学）提供了宝贵的建议。出于开放获取的目的，知识共享署名（CC BY）许可证适用于本次提交产生的任何作者接受的稿件版本。FundingWJB获得了乳腺癌Now（2015NovPhD572），英国癌症研究（A25922）和BBSRC（BB/Y513970/1）的资助。

WJB and ANH received funding from the MRC (MR/X018067/1). ANH received funding from the BBSRC (BB/V000071/1). SPF received funding from the Pro Cancer Research Fund. NS received a scholarship from the Royal Thai Government. SCS, CLHH, and APJ received funding from the British Heart Foundation (PG/14/79/31102 and PG/19/59/34582).Author informationAuthors and AffiliationsDepartment of Biology, University of York, York, UKTheresa K.

WJB和ANH获得了MRC（MR/X018067/1）的资助。ANH收到了BBSRC（BB/V000071/1）的资助。SPF获得了癌症研究基金的资助。NS获得了泰国皇家政府的奖学金。SCS，CLHH和APJ获得了英国心脏基金会的资助（第14/79/31102页和第19/59/34582页）。作者信息作者和附属机构约克大学生物学系，约克，英国特蕾莎K。

Leslie, Andrew D. James, Michaela Nelson, Nattanan Sajjaboontawee, Alina L. Capatina, Andrew N. Holding, Sangeeta Chawla & William J. BrackenburyYork Biomedical Research Institute, University of York, York, UKTheresa K. Leslie, Andrew D. James, Michaela Nelson, Nattanan Sajjaboontawee, Alina L. Capatina, Andrew N.

莱斯利（Leslie）、安德鲁·詹姆斯（Andrew D.James）、迈克尔·尼尔森（Michaela Nelson）、纳塔南·萨贾布恩·塔维（Nattana Sajjaboontawee）、艾琳娜·卡帕蒂娜（Alina L.Capatina）、安德鲁·霍尔德（Andrew N.Holding）、桑吉塔·查拉（Sangeeta Chawla）和威廉·布拉肯·布里约克（William J.BrackenburyYork）生物医学研究所（University of York）、约克（Uktresa K.）莱斯利（Leslie）、安德鲁·詹姆斯。

Holding, Sangeeta Chawla & William J. BrackenburyDivision of Cancer Biology, Institute of Cancer Research, London, UKAurelien Tripp, Mar Arias Garcia, Melina Beykou, Chris Bakal & George Pou.

Holding，Sangeeta Chawla和William J.BrackenburyDivision癌症生物学，伦敦癌症研究所，Ukarelien Tripp，Mar Arias Garcia，Melina Beykou，Chris Bakal和George Pou。

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PubMed Google ScholarContributionsTKL, SC, WJB: study conception and design; data collection; analysis and interpretation of results; manuscript preparation; review of results and approval of manuscript. AT, ADJ, SPF, MN, NS, ALC, MT, WF, MAG, MB: data collection; analysis and interpretation of results; manuscript preparation; review of results and approval of manuscript.

PubMed谷歌学术贡献STKL，SC，WJB：研究概念和设计；数据收集；结果的分析和解释；稿件准备；审查结果并批准稿件。AT，ADJ，SPF，MN，NS，ALC，MT，WF，MAG，MB：数据收集；结果的分析和解释；稿件准备；审查结果并批准稿件。

SCS, ER, VS, CB, GP, MBAD, APJ, HRM, CLHH, ANH: analysis and interpretation of results; manuscript preparation; review of results and approval of manuscript.Corresponding authorCorrespondence to.

SCS，ER，VS，CB，GP，MBA，APJ，HRM，CLHH，ANH：结果的分析和解释；稿件准备；审查结果并批准稿件。对应作者对应。

William J. Brackenbury.Ethics declarations

威廉·布莱肯伯里（WilliamJ.Brackenbury）。道德宣言

Competing interests

相互竞争的利益

MBAD holds shares in Celex Oncology Innovations Ltd. VS is one of the founders of the Breast Cancer Now Tissue Bank.

MBA持有Celex Oncology Innovations Ltd.的股份。VS是现在乳腺癌组织库的创始人之一。

Ethics approval and consent to participate

道德批准和同意参与

All animal procedures were carried out after approval by the University of York Animal Welfare and Ethical Review Body and under the authority of a UK Home Office Project Licence and associated Personal Licences. Human tissue experiments were conducted in accordance with the ethical standards of the Declaration of Helsinki and according to national and international guidelines and were approved by the University of York Ethical Review Process.

。人体组织实验是根据赫尔辛基宣言的道德标准以及国家和国际准则进行的，并得到了约克大学道德审查程序的批准。

Patient samples and data from the Breast Cancer Now Tissue Bank (BCNTB) were covered by UK NHS REC 21/EE/0072. Informed consent was obtained from all subjects..

英国NHS REC 21/EE/0072涵盖了来自乳腺癌组织库（BCNTB）的患者样本和数据。所有受试者均获得知情同意。。

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Reprints and permissionsAbout this articleCite this articleLeslie, T.K., Tripp, A., James, A.D. et al. A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis.

转载和许可本文引用本文Leslie，T.K.，Tripp，A.，James，A.D。等人。一种新的Nav1.5依赖性反馈机制，驱动乳腺癌转移中糖酵解酸化。

Oncogene (2024). https://doi.org/10.1038/s41388-024-03098-xDownload citationReceived: 20 November 2023Revised: 29 June 2024Accepted: 04 July 2024Published: 25 July 2024DOI: https://doi.org/10.1038/s41388-024-03098-xShare 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.

癌基因（2024）。https://doi.org/10.1038/s41388-024-03098-xDownload引文接收日期：2023年11月20日修订日期：2024年6月29日接受日期：2024年7月4日发布日期：2024年7月25日OI：https://doi.org/10.1038/s41388-024-03098-xShare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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