Scientific Reports：酸性感应离子通道3是控制癌症胶质母细胞瘤干细胞生长的新的潜在治疗靶点-动脉网

Scientific Reports：Acid-sensing ion channel 3 is a new potential therapeutic target for the control of glioblastoma cancer stem cells growth

Nature 等信源发布 2024-09-03 13:42



可切换为仅中文







AbstractGlioblastoma (GBM) is the most common malignant primary brain cancer that, despite recent advances in the understanding of its pathogenesis, remains incurable. GBM contains a subpopulation of cells with stem cell-like properties called cancer stem cells (CSCs). Several studies have demonstrated that CSCs are resistant to conventional chemotherapy and radiation thus representing important targets for novel anti-cancer therapies.

摘要胶质母细胞瘤（GBM）是最常见的恶性原发性脑癌，尽管对其发病机制的理解最近取得了进展，但仍然无法治愈。GBM含有具有干细胞样特性的细胞亚群，称为癌症干细胞（CSC）。一些研究表明，CSCs对常规化疗和放疗具有抗性，因此是新型抗癌疗法的重要靶点。

Proton sensing receptors expressed by CSCs could represent important factors involved in the adaptation of tumours to the extracellular environment. Accordingly, the expression of acid-sensing ion channels (ASICs), proton-gated sodium channels mainly expressed in the neurons of peripheral (PNS) and central nervous system (CNS), has been demonstrated in several tumours and linked to an increase in cell migration and proliferation.

CSCs表达的质子感应受体可能是肿瘤适应细胞外环境的重要因素。因此，酸敏感离子通道（ASIC）的表达，主要在外周（PNS）和中枢神经系统（CNS）的神经元中表达的质子门控钠通道，已在几种肿瘤中得到证实，并与细胞迁移和增殖的增加有关。

In this paper we report that the ASIC3 isoform, usually absent in the CNS and present in the PNS, is enriched in human GBM CSCs while poorly expressed in the healthy human brain. We propose here a novel therapeutic strategy based on the pharmacological activation of ASIC3, which induces a significant GBM CSCs damage while being non-toxic for neurons.

在本文中，我们报告说，通常在中枢神经系统中不存在且存在于PNS中的ASIC3亚型在人类GBM CSC中富集，而在健康人脑中表达较差。我们在这里提出了一种基于ASIC3药理激活的新型治疗策略，该策略可诱导显着的GBM CSC损伤，同时对神经元无毒。

This approach might offer a promising and appealing new translational pathway for the treatment of glioblastoma. .

这种方法可能为胶质母细胞瘤的治疗提供一种有前途且有吸引力的新翻译途径。

IntroductionCancer is a relevant public health problem with increasing morbidity and mortality and is a serious threat to human health. In 2020, there were an estimated 19.3 million new cases of cancer worldwide1. Glioblastoma (GBM) is the most common malignant brain tumor and accounts for more than 50% of all gliomas2.

引言癌症是一个相关的公共卫生问题，发病率和死亡率不断增加，对人类健康构成严重威胁。2020年，全世界估计有1930万新发癌症病例1。胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，占所有胶质瘤的50%以上2。

Ninety-five percent of all GBMs are primary (arising de novo), whereas 5% arise from less malignant precursor gliomas. GBM is characterized by high proliferation and infiltration proficiency, and despite recent advances, it remains incurable, with a poor prognosis and a median survival time of approximately 15 months3.

所有GBM中有95%是原发性的（从头产生），而5%来自恶性程度较低的前体神经胶质瘤。GBM的特征是高增殖和浸润能力，尽管最近取得了进展，但它仍然无法治愈，预后不良，中位生存时间约为15个月3。

GBM complexity is reflected by its cellular and molecular heterogeneity; thus, GBM can be classified into the proneural (PN), classical (CL) and mesenchymal (MES) subtypes depending on its aggressiveness4. One of the most infamous traits of GBM is its resistance to conventional therapies and the absence of an effective antitumor strategy.

GBM的复杂性反映在其细胞和分子异质性上；因此，根据其侵袭性，GBM可分为神经（PN），经典（CL）和间充质（MES）亚型4。GBM最臭名昭著的特征之一是它对常规疗法的抵抗力以及缺乏有效的抗肿瘤策略。

Despite all these efforts, the survival of patients after one year from diagnosis remains low5. Solid tumours, including GBM, are characterized by a high metabolic rate and limited blood supply. In this context, tumor cells switch to aerobic glycolysis, generating considerable amounts of energy to support their rapid growth.

尽管做出了所有这些努力，但诊断后一年后患者的生存率仍然很低5。包括GBM在内的实体瘤的特征在于高代谢率和有限的血液供应。在这种情况下，肿瘤细胞转向有氧糖酵解，产生大量能量以支持其快速生长。

This results in the continuous generation of metabolic acids, producing acidosis in tumor tissues6. The tumor pH ranges from 6.0 to 6.9, with a mean of approximately 6.8, and acidosis has been linked to tumor invasion and metastasis7,8. While acidity is deleterious to normal cells, long time coevolution of tumor cells with the host has enabled them to be more adaptable to the acidic microenvironment9.

这导致代谢酸的持续产生，在肿瘤组织中产生酸中毒6。肿瘤pH值范围为6.0至6.9，平均约为6.8，酸中毒与肿瘤侵袭和转移有关7,8。。

Accumulating evidence indicates that the acidity of the tumor microenvironment is as.

越来越多的证据表明，肿瘤微环境的酸度为as。

Data availability

数据可用性

The authors declare that the data supporting the findings of this study are available within the article and its supplementary information. Any other associated data supporting the findings of this study are available from the corresponding author upon request. The datasets analysed during the current study are available at https://www.betastasis.com/glioma/tcga_gbm/..

作者声明，本文及其补充信息中提供了支持本研究结果的数据。支持本研究结果的任何其他相关数据可应要求从通讯作者处获得。当前研究期间分析的数据集可在https://www.betastasis.com/glioma/tcga_gbm/..

ReferencesSung, H. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).Article

ReferencesSung，H.等人，《2020年全球癌症统计：全球癌症协会对185个国家36种癌症的全球发病率和死亡率的估计》。CA Cancer J.Clin。71209-249（2021）。文章

PubMed

Google Scholar

谷歌学者

Reifenberger, G., Wirsching, H.-G., Knobbe-Thomsen, C. B. & Weller, M. Advances in the molecular genetics of gliomas—Implications for classification and therapy. Nat. Rev. Clin. Oncol. 14, 434–452 (2017).Article

Reifenberger，G.，Wirsching，H.-G.，Knobbe-Thomsen，C.B。＆Weller，M。胶质瘤分子遗传学进展对分类和治疗的影响。国家修订临床。Oncol公司。14434-452（2017）。文章

PubMed

Google Scholar

谷歌学者

Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).Article

Stupp，R。等人。放射治疗加伴随和辅助替莫唑胺治疗胶质母细胞瘤。N、英语。J、医学352987-996（2005）。文章

PubMed

Google Scholar

谷歌学者

Hu, Y. et al. Neural network learning defines glioblastoma features to be of neural crest perivascular or radial glia lineages. Sci. Adv. 8, 6340 (2022).Article

Hu，Y。等人。神经网络学习将胶质母细胞瘤特征定义为神经嵴血管周围或放射状胶质细胞谱系。科学。Adv.86340（2022年）。文章

Google Scholar

谷歌学者

Rodríguez-Camacho, A. et al. Glioblastoma treatment: State-of-the-art and future perspectives. Int. J. Mol. Sci. 23(13), 7207 (2022).Article

Rodríguez-Camacho，A。等。胶质母细胞瘤治疗：现状和未来前景。Int.J.Mol.Sci。23（13），7207（2022）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Corbet, C. & Feron, O. Tumour acidosis: From the passenger to the driver’s seat. Nat. Rev. Cancer 17(10), 577–593 (2017).Article

Corbet，C。＆Feron，O。肿瘤性酸中毒：从乘客到驾驶员座椅。《自然评论》癌症17（10），577-593（2017）。文章

PubMed

Google Scholar

谷歌学者

Ibrahim-Hashim, A. & Estrella, V. Acidosis and cancer: From mechanism to neutralization. Cancer Metastasis Rev. 38, 149–155 (2019).Article

。癌症转移Rev.38149-155（2019）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Estrella, V. et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 73, 1524–1535 (2013).Article

Estrella，V。等人。由肿瘤微环境产生的酸度驱动局部侵袭。癌症研究731524-1535（2013）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Damaghi, M., Wojtkowiak, J. W. & Gillies, R. J. pH sensing and regulation in cancer. Front. Physiol. 4, 370 (2013).Article

Damaghi，M.，Wojtkowiak，J.W。和Gillies，R.J。癌症中的pH传感和调节。正面。生理学。4370（2013）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Hjelmeland, A. B. et al. Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ. 18(5), 829–840 (2011).Article

Hjelmeland，A.B.等人。酸性应激促进胶质瘤干细胞表型。细胞死亡不同。18（5），829-840（2011）。文章

PubMed

Google Scholar

谷歌学者

Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L. L. & Rich, J. N. Cancer stem cells in glioblastoma. Genes Dev. 29, 1203–1217 (2015).Article

Lathia，J.D.，Mack，S.C.，Mulkarns-Hubert，E.E.，Valentim，C.L.L.＆Rich，J.N。胶质母细胞瘤中的癌症干细胞。基因发展291203-1217（2015）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lytle, N. K., Barber, A. G. & Reya, T. Stem cell fate in cancer growth, progression and therapy resistance. Nat. Rev. Cancer 18(11), 669–680 (2018).Article

Lytle，N.K.，Barber，A.G。＆Reya，T。干细胞在癌症生长，进展和治疗抵抗中的命运。《自然评论》癌症18（11），669-680（2018）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Galli, R. et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021 (2004).Article

。癌症研究647011-7021（2004）。文章

PubMed

Google Scholar

谷歌学者

Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414(6859), 105–111 (2001).Article

Reya，T.，Morrison，S.J.，Clarke，M.F。＆Weissman，I.L。干细胞，癌症和癌症干细胞。自然414（6859），105-111（2001）。文章

ADS

PubMed

Google Scholar

谷歌学者

Piccirillo, S. G. M. et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444(7120), 761–765 (2006).Article

Piccirillo，S.G.M.等人。骨形态发生蛋白抑制人脑肿瘤起始细胞的致瘤潜力。《自然》444（7120），761-765（2006）。文章

ADS

PubMed

Google Scholar

谷歌学者

Prevarskaya, N., Skryma, R. & Shuba, Y. Ion channels and the hallmarks of cancer. Trends Mol. Med. 16, 107–121 (2010).Article

Prevarskaya，N.，Skryma，R。＆Shuba，Y。离子通道和癌症的标志。趋势分子医学杂志16107-121（2010）。文章

PubMed

Google Scholar

谷歌学者

Liu, C., Zhu, L. L., Xu, S. G., Ji, H. L. & Li, X. M. ENaC/DEG in tumor development and progression. J. Cancer 7, 1888 (2016).Article

Liu，C.，Zhu，L.L.，Xu，S.G.，Ji，H.L。＆Li，X.M。ENaC/DEG在肿瘤发展和进展中的作用。J、癌症71888（2016）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Gründer, S., Vanek, J. & Pissas, K. P. Acid-sensing ion channels and downstream signalling in cancer cells: Is there a mechanistic link?. Pflügers Arch.-Eur. J. Physiol. 4, 1–14 (2024).

Gründer，S.，Vanek，J。＆Pissas，K.P。癌细胞中的酸敏感离子通道和下游信号传导：是否存在机械联系？。Pflügers拱门-Eur.J.Physiol。4，1-14（2024）。

Google Scholar

谷歌学者

Chen, B., Liu, J., Ho, T. T., Ding, X. & Mo, Y. Y. ERK-mediated NF-κB activation through ASIC1 in response to acidosis. Oncogene 512(5), e279–e279 (2016).Article

Chen，B.，Liu，J.，Ho，T。T.，Ding，X。＆Mo，Y。Y。ERK通过ASIC1介导NF-κB活化以应对酸中毒。。文章

Google Scholar

谷歌学者

King, P. et al. Regulation of gliomagenesis and stemness through acid sensor ASIC1a. Int. J. Oncol. 59, 1–15 (2021).Article

King，P。等人。通过酸传感器ASIC1a调节胶质瘤发生和干性。内景J.Oncol。59，1-15（2021）。文章

Google Scholar

谷歌学者

Tian, Y. et al. Glioblastoma cancer stem cell lines express functional acid sensing ion channels ASIC1a and ASIC3. Sci. Rep. 7, 1–14 (2017).Article

Tian，Y。等人。胶质母细胞瘤癌症干细胞系表达功能性酸敏感离子通道ASIC1a和ASIC3。科学。代表7，1-14（2017）。文章

Google Scholar

谷歌学者

Wemmie, J. A. et al. Acid-sensing ion channels in pain and disease. Nat. Rev. Neurosci. 14(7), 461–471 (2013).Article

Wemmie，J.A.等人，《疼痛和疾病中的酸敏感离子通道》。神经科学杂志。14（7），461-471（2013）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Boscardin, E., Alijevic, O., Hummler, E., Frateschi, S. & Kellenberger, S. The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na+ channel (ENaC): IUPHAR review 19. Br. J. Pharmacol. 173, 2671–2701 (2016).Article

Boscardin，E.，Alijevic，O.，Hummler，E.，Frateschi，S。＆Kellenberger，S。酸敏感离子通道（ASIC）和上皮Na+通道（ENaC）的功能和调节：IUPHAR评论19。Br.J.药理学。1732671-2701（2016）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wemmie, J. A. et al. Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning. J. Neurosci. 23, 5496–5502 (2003).Article

Wemmie，J.A。等人。酸感应离子通道1位于具有高突触密度的大脑区域，并有助于恐惧条件反射。J、神经科学。235496-5502（2003）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Baron, A., Voilley, N., Lazdunski, M. & Lingueglia, E. Acid sensing ion channels in dorsal spinal cord neurons. J. Neurosci. 28, 1498–1508 (2008).Article

Baron，A.，Voilley，N.，Lazdunski，M。＆Lingueglia，E。脊髓背侧神经元中的酸敏感离子通道。J、神经科学。281498-1508（2008）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Deval, E. et al. ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J. 27, 3047–3055 (2008).Article

Deval，E.等人，ASIC3，一种酸性和原发性炎性疼痛的传感器。EMBO J.273047–3055（2008）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lin, Y. W. et al. Identification and characterization of a subset of mouse sensory neurons that express acid-sensing ion channel 3. Neuroscience 151, 544–557 (2008).Article

Lin，Y.W.等人。表达酸敏感离子通道3的小鼠感觉神经元子集的鉴定和表征。神经科学151544-557（2008）。文章

PubMed

Google Scholar

谷歌学者

Zhang, Z. et al. Acid-sensing ion channel 1a modulation of apoptosis in acidosis-related diseases: Implications for therapeutic intervention. Cell Death Discov. 9(1), 330 (2023).Article

Zhang，Z.等。酸敏感离子通道1a对酸中毒相关疾病细胞凋亡的调节：对治疗干预的意义。细胞死亡发现。9（1），330（2023）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, Y., Zhou, H., Sun, Y. & Huang, Y. Acid-sensing ion channel 1: Potential therapeutic target for tumor. Biomed. Pharmacother. 155, 113835 (2022).Article

Wang，Y.，Zhou，H.，Sun，Y。＆Huang，Y。酸敏感离子通道1：肿瘤的潜在治疗靶点。生物医学。药剂师。155113835（2022）。文章

PubMed

Google Scholar

谷歌学者

Gupta, S. C. et al. Regulation of breast tumorigenesis through acid sensors. Oncogene 35(31), 4102–4111 (2016).Article

Gupta，S.C.等人。通过酸传感器调节乳腺肿瘤发生。癌基因35（31），4102-4111（2016）。文章

PubMed

Google Scholar

谷歌学者

Zhu, S. et al. ASIC1 and ASIC3 contribute to acidity-induced EMT of pancreatic cancer through activating Ca2+/RhoA pathway. Cell Death Dis. 8(5), e2806–e2806 (2017).Article

Zhu，S。等人。ASIC1和ASIC3通过激活Ca2+/RhoA途径促进酸性诱导的胰腺癌EMT。细胞死亡Dis。8（5），e2806–e2806（2017）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Berdiev, B. K. et al. Acid-sensing ion channels in malignant gliomas. J. Biol. Chem. 278, 15023–15034 (2003).Article

Berdiev，B.K.等。恶性胶质瘤中的酸敏感离子通道。J、生物。。27815023-15034（2003）。文章

PubMed

Google Scholar

谷歌学者

Litan, A. & Langhans, S. A. Cancer as a channelopathy: Ion channels and pumps in tumor development and progression. Front. Cell. Neurosci. 9, 132394 (2015).Article

Litan，A。＆Langhans，S.A。癌症作为一种通道病：离子通道和泵在肿瘤发展和进展中的作用。正面。细胞。神经科学。9132394（2015）。文章

Google Scholar

谷歌学者

Yang, M. & Brackenbury, W. J. Membrane potential and cancer progression. Front. Physiol. 4, 185 (2013).Article

。正面。生理学。4185（2013）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Niklasson, M. et al. Membrane-depolarizing channel blockers induce selective glioma cell death by impairing nutrient transport and unfolded protein/amino acid responses. Cancer Res. 77, 1741–1752 (2017).Article

Niklasson，M。等人。膜去极化通道阻滞剂通过损害营养转运和未折叠的蛋白质/氨基酸反应诱导选择性神经胶质瘤细胞死亡。癌症研究771741-1752（2017）。文章

PubMed

Google Scholar

谷歌学者

Li, W. G., Yu, Y., Zhang, Z. D., Cao, H. & Xu, T. L. ASIC3 channels integrate agmatine and multiple inflammatory signals through the nonproton ligand sensing domain. Mol. Pain 6, 1744–8069 (2010).Article

Li，W.G.，Yu，Y.，Zhang，Z.D.，Cao，H。＆Xu，T.L。ASIC3通道通过非质子配体感应域整合胍丁胺和多种炎症信号。摩尔疼痛61744-8069（2010）。文章

Google Scholar

谷歌学者

Agharkar, A. S. & Gonzales, E. B. 4-Chlorophenylguanidine is an ASIC3 agonist and positive allosteric modulator. J. Pharmacol. Sci. 133, 184–186 (2017).Article

Agharkar，A.S。和Gonzales，E.B。4-氯苯胍是一种ASIC3激动剂和正变构调节剂。J、药理学。科学。133184-186（2017）。文章

PubMed

Google Scholar

谷歌学者

Callejo, G. et al. In silico screening of GMQ-like compounds reveals guanabenz and sephin1 as new allosteric modulators of acid-sensing ion channel 3. Biochem. Pharmacol. 174, 113834 (2020).Article

Callejo，G。等人在GMQ样化合物的计算机筛选中发现guanabenz和sephin1是酸敏感离子通道3的新变构调节剂。生物化学。药理学。174113834（2020）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yu, Y. et al. A nonproton ligand sensor in the acid-sensing ion channel. Neuron 68, 61–72 (2010).Article

。神经元68,61-72（2010）。文章

PubMed

Google Scholar

谷歌学者

Besson, T., Lingueglia, E. & Salinas, M. Pharmacological modulation of acid-sensing ion channels 1a and 3 by amiloride and 2-guanidine-4-methylquinazoline (GMQ). Neuropharmacology 125, 429–440 (2017).Article

。神经药理学125429-440（2017）。文章

PubMed

Google Scholar

谷歌学者

Delaunay, A. et al. Human ASIC3 channel dynamically adapts its activity to sense the extracellular pH in both acidic and alkaline directions. Proc. Natl. Acad. Sci. USA 109, 13124–13129 (2012).Article

Delaunay，A。等人。人类ASIC3通道动态调整其活性，以感知酸性和碱性方向的细胞外pH。程序。纳特尔。阿卡德。科学。。文章

ADS

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Foster, V. S. et al. Acid-sensing ion channels: Expression and function in resident and infiltrating immune cells in the central nervous system. Front. Cell. Neurosci. 15, 738043 (2021).Article

Foster，V.S.等人，《酸敏感离子通道：在中枢神经系统的常驻和浸润免疫细胞中的表达和功能》。正面。细胞。神经科学。15738043（2021）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Minghua, L. et al. Acid-sensing ion channels in acidosis-induced injury of human brain neurons. J. Cereb. Blood Flow Metab. 30, 1247–1260 (2010).Article

Minghua，L。等人。酸中毒引起的人脑神经元损伤中的酸敏感离子通道。J、塞雷布。血流代谢。301247-1260（2010）。文章

Google Scholar

谷歌学者

Bortner, C. D., Gómez-Angelats, M. & Cidlowski, J. A. Plasma membrane depolarization without repolarization is an early molecular event in anti-Fas-induced apoptosis. J. Biol. Chem. 276, 4304–4314 (2001).Article

Bortner，C.D.，Gómez-Angelats，M。＆Cidlowski，J.A。质膜去极化而不复极化是抗Fas诱导的细胞凋亡的早期分子事件。J、生物。。2764304-4314（2001）。文章

PubMed

Google Scholar

谷歌学者

Narayanan, A. et al. The proneural gene ASCL1 governs the transcriptional subgroup affiliation in glioblastoma stem cells by directly repressing the mesenchymal gene NDRG1. Cell Death Differ. 26(9), 1813–1831 (2019).Article

Narayanan，A。等人。神经原基因ASCL1通过直接抑制间充质基因NDRG1来控制胶质母细胞瘤干细胞中的转录亚组隶属关系。细胞死亡不同。26（9），1813-1831（2019）。文章

PubMed

Google Scholar

谷歌学者

Di Tomaso, T. et al. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin. Cancer Res. 16, 800–813 (2010).Article

Di Tomaso，T.等人。从胶质母细胞瘤患者中分离的癌症干细胞的免疫生物学表征。临床。癌症研究16800-813（2010）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

De Ceglia, R. et al. Down-sizing of neuronal network activity and density of presynaptic terminals by pathological acidosis are efficiently prevented by diminazene aceturate. Brain Behav. Immun. 45, 263–276 (2015).Article

De Ceglia，R。等人。通过病理性酸中毒，神经元网络活性和突触前终末密度的降低可通过二咪唑乙酸酯有效预防。大脑行为。免疫。45263-276（2015）。文章

PubMed

Google Scholar

谷歌学者

Pahari S., Sun L., & Alexov E. PKAD: A database of experimentally measured pKa values of ionizable groups in proteins. Database baz024 (2019)Yoder, N. & Gouaux, E. The his-gly motif of acid-sensing ion channels resides in a reentrant ‘loop’ implicated in gating and ion selectivity. Elife 9, 1–18 (2020).Article .

Pahari S.，Sun L.，＆Alexov E.PKAD：蛋白质中可电离基团的实验测量pKa值的数据库。数据库baz024（2019）Yoder，N。＆Gouaux，E。酸敏感离子通道的his-gly基序位于一个与门控和离子选择性有关的折返“环”中。Elife 9,1-18（2020）。文章。

Google Scholar

谷歌学者

Abraham, M. J. et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2, 19–25 (2015).Article

Abraham，M.J.等人，《GROMACS：通过从笔记本电脑到超级计算机的多级并行进行高性能分子模拟》。SoftwareX 1-2、19-25（2015）。文章

ADS

Google Scholar

谷歌学者

Schmid, N. et al. Definition and testing of the GROMOS force-field versions 54A7 and 54B7. Eur. Biophys. J. 40, 843–856 (2011).Article

Schmid，N.等人，《GROMOS力场版本54A7和54B7的定义和测试》。欧洲生物物理。J、 40843-856（2011）。文章

PubMed

Google Scholar

谷歌学者

Sanner, M. F. Python: A programming language for software integration and development. J. Mol. Graph Model. 17, 57–61 (1999).PubMed

Sanner，M.F.Python：一种用于软件集成和开发的编程语言。J、分子图模型。17，57-61（1999）。PubMed出版社

Google Scholar

谷歌学者

Trott, O. & Olson, A. J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31(2), 455–461 (2010).Article

Trott，O.＆Olson，A.J。AutoDock Vina：通过新的评分函数，有效的优化和多线程来提高对接的速度和准确性。J、计算机。。31（2），455-461（2010）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Morris, G. M. et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 30, 2785–2791 (2009).Article

Morris，G.M.等人。AutoDock4和AutoDockTools4：具有选择性受体灵活性的自动对接。J、计算机。。302785-2791（2009）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Casella, G. et al. IL4 induces IL6-producing M2 macrophages associated to inhibition of neuroinflammation in vitro and in vivo. J. Neuroinflamm. 13, 1–10 (2016).Article

Casella，G。等人，IL4在体外和体内诱导产生IL6的M2巨噬细胞，这些巨噬细胞与抑制神经炎症有关。J、神经炎症。13,1-10（2016）。文章

Google Scholar

谷歌学者

Rahman, M. et al. Neurosphere and adherent culture conditions are equivalent for malignant glioma stem cell lines. Anat. Cell Biol. 48, 25–35 (2015).Article

Rahman，M。等人。神经球和贴壁培养条件对于恶性胶质瘤干细胞系是等效的。阿纳特。细胞生物学。48,25-35（2015）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Cortés Franco K.D. et al. Aggressive migration in acidic pH of a glioblastoma cancer stem cell line in vitro is independent of ASIC and KCa3.1 ion channels, but involves phosphoinositide 3-kinase. Pflugers Arch. Eur. J. Physiol. 475, 405–416 (2023)Zhou, Z. H. et al. The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis.

Cortés Franco K.D.等人。体外胶质母细胞瘤癌症干细胞系在酸性pH下的侵袭性迁移与ASIC和KCa3.1离子通道无关，但涉及磷酸肌醇3-激酶。Pflugers拱门。Eur.J.Physiol。475405–416（2023）Zhou，Z.H.等人。酸敏感离子通道ASIC2通过激活钙调神经磷酸酶/NFAT1轴促进酸中毒下结直肠癌的侵袭和转移。

J. Exp. Clin. Cancer Res. 36, 1–12 (2017).Article .

J、实验临床。癌症研究36,1-12（2017）。文章。

Google Scholar

谷歌学者

Qian, H. Y. et al. Metformin attenuates bone cancer pain by reducing TRPV1 and ASIC3 expression. Front. Pharmacol. 12, 713944 (2021).Article

Qian，H.Y.等人。二甲双胍通过降低TRPV1和ASIC3的表达来减轻骨癌疼痛。正面。药理学。12713944（2021）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Poon, M. T. C., Bruce, M., Simpson, J. E., Hannan, C. J. & Brennan, P. M. Temozolomide sensitivity of malignant glioma cell lines—A systematic review assessing consistencies between in vitro studies. BMC Cancer 21, 1–9 (2021).Article

Poon，M.T.C.，Bruce，M.，Simpson，J.E.，Hannan，C.J。＆Brennan，P.M。替莫唑胺对恶性胶质瘤细胞系的敏感性-评估体外研究之间一致性的系统评价。BMC癌症21,1-9（2021）。文章

Google Scholar

谷歌学者

Cidado, J. et al. Ki-67 is required for maintenance of cancer stem cells but not cell proliferation. Oncotarget 7, 6281 (2016).Article

Cidado，J。等人。Ki-67是维持癌症干细胞而不是细胞增殖所必需的。Oncotarget 76281（2016）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wu, Y. et al. Acid-sensing ion channels contribute to the effect of extracellular acidosis on proliferation and migration of A549 cells. Tumor Biol. 39, 12 (2017).Article

Wu，Y。等人。酸敏感离子通道有助于细胞外酸中毒对A549细胞增殖和迁移的影响。肿瘤生物学。39，12（2017）。文章

Google Scholar

谷歌学者

Alijevic, O. & Kellenberger, S. Subtype-specific modulation of acid-sensing ion channel (ASIC) function by 2-guanidine-4-methylquinazoline. J. Biol. Chem. 287, 36059–36070 (2012).Article

Alijevic，O。＆Kellenberger，S。通过2-胍-4-甲基喹唑啉对酸敏感离子通道（ASIC）功能的亚型特异性调节。J、生物。。28736059-36070（2012）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Diochot, S. et al. A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J. 23, 1516–1525 (2004).Article

Diochot，S。等人。一种新的海葵肽APETx2抑制ASIC3，ASIC3是感觉神经元中主要的酸敏感通道。EMBO J.231516–1525（2004）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Beier, D. et al. Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res. 68, 5706–5715 (2008).Article

Beier，D。等人。替莫唑胺优先消耗胶质母细胞瘤中的癌症干细胞。癌症研究685706-5715（2008）。文章

PubMed

Google Scholar

谷歌学者

Wu, Y., Franzmeier, S., Liesche-Starnecker, F. & Schlegel, J. Enhanced sensitivity to ALDH1A3-dependent ferroptosis in TMZ-resistant glioblastoma cells. Cells 12(21), 2522 (2023).Article

Wu，Y.，Franzmeier，S.，Liesche-Starnecker，F。＆Schlegel，J。在TMZ抗性胶质母细胞瘤细胞中增强对ALDH1A3依赖性铁浓化的敏感性。细胞12（21），2522（2023）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yuan, X. et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23, 9392–9400 (2004).Article

袁，X。等。从成人多形性胶质母细胞瘤中分离癌症干细胞。癌基因239392-9400（2004）。文章

PubMed

Google Scholar

谷歌学者

Laks, D. R. et al. Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem cells 27, 980–987 (2009).Article

Laks，D.R.等人。神经球形成是恶性胶质瘤临床结果的独立预测因子。干细胞27980-987（2009）。文章

PubMed

Google Scholar

谷歌学者

Hu, Y. & Gordon, K. S. ELDA: Extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J. Immunol. Methods 347, 70–78 (2009).Article

Hu，Y。＆Gordon，K。S。ELDA：极端有限稀释分析，用于比较干细胞和其他测定中耗尽和富集的群体。J、免疫。方法347,70-78（2009）。文章

PubMed

Google Scholar

谷歌学者

Deval, E. et al. Acid-sensing ion channels in postoperative pain. J. Neurosci. 31, 6059–6066 (2011).Article

Deval，E。等人。术后疼痛中的酸敏感离子通道。J、神经科学。316059–6066（2011）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, D. et al. Effects of hypoxia and ASIC3 on nucleus pulposus cells: From cell behavior to molecular mechanism. Biomed. Pharmacother. 117, 109061 (2019).Article

Wang，D.等。缺氧和ASIC3对髓核细胞的影响：从细胞行为到分子机制。生物医学。药剂师。117109061（2019）。文章

PubMed

Google Scholar

谷歌学者

Walker, K. & Hjelmeland, A. Method for efficient transduction of cancer stem cells. J. Cancer Stem Cell Res. 2, 1 (2014).Article

Walker，K。＆Hjelmeland，A。有效转导癌症干细胞的方法。J、癌症干细胞研究2,1（2014）。文章

Google Scholar

谷歌学者

Rooj, A. K. et al. Glioma-specific cation conductance regulates migration and cell cycle progression. J. Biol. Chem. 287, 4053–4065 (2012).Article

Rooj，A.K.等人。胶质瘤特异性阳离子电导调节迁移和细胞周期进程。J、生物。。2874053-4065（2012）。文章

PubMed

Google Scholar

谷歌学者

Kapoor, N. et al. Knockdown of ASIC1 and epithelial sodium channel subunits inhibits glioblastoma whole cell current and cell migration. J. Biol. Chem. 284, 24526–24541 (2009).Article

敲除ASIC1和上皮钠通道亚基可抑制胶质母细胞瘤的全细胞电流和细胞迁移。J、生物。。28424526-24541（2009）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kellenberger, S. & Schild, L. International Union of Basic and Clinical Pharmacology. XCI. Structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel. Pharmacol. Rev. 67, 1–35 (2015).Article

Kellenberger，S。和Schild，L。国际基础和临床药理学联合会。XCI公司。酸敏感离子通道和上皮Na+通道的结构，功能和药理学。药理学。第67版，第1-35页（2015年）。文章

PubMed

Google Scholar

谷歌学者

Cheng, Q. et al. Novel insights into ion channels in cancer stem cells (review). Int. J. Oncol. 53, 1435–1441 (2018).PubMed

Cheng，Q。等人。对癌症干细胞中离子通道的新见解（综述）。内景J.Oncol。531435-1441（2018）。PubMed出版社

Google Scholar

谷歌学者

Takayasu, T., Kurisu, K., Esquenazi, Y. & Ballester, L. Y. Ion channels and their role in the pathophysiology of gliomas. Mol. Cancer Ther. 19, 1959–1969 (2020).Article

Takayasu，T.，Kurisu，K.，Esquenazi，Y。＆Ballester，L.Y。离子通道及其在神经胶质瘤病理生理学中的作用。分子癌症治疗。1959年至1969年（2020年）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Pollak, J. et al. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy. PLoS One 12, e0172884 (2017).Article

Pollak，J。等人。胶质母细胞瘤干细胞中离子通道的表达模式，对恶性肿瘤具有功能和治疗意义。PLoS One 12，e0172884（2017）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Pöhlmann, J. et al. High costs, low quality of life, reduced survival, and room for improving treatment: An analysis of burden and unmet needs in glioma. Front. Oncol. 14, 1368606 (2024).Article

Pöhlmann，J.等人，《高成本，低生活质量，生存率降低和改善治疗空间：胶质瘤负担和未满足需求的分析》。正面。Oncol公司。141368606（2024）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Li, W. G. & Xu, T. L. ASIC3 channels in multimodal sensory perception. ACS Chem. Neurosci. 2, 26–37 (2011).Article

Li，W.G。＆Xu，T.L。多模态感觉知觉中的ASIC3通道。ACS化学。神经科学。2，26-37（2011）。文章

PubMed

Google Scholar

谷歌学者

Dulai, J. S., Smith, E. S. J. & Rahman, T. Acid-sensing ion channel 3: An analgesic target. Channels 15, 94–127 (2021).Article

Dulai，J.S.，Smith，E.S.J.＆Rahman，T。酸敏感离子通道3：镇痛靶标。频道15、94–127（2021）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Download referencesAcknowledgementsWe thank Dr. Dey Sumit Kumar for his technical assistance in LVs production.Author informationAuthor notesSimone BruscoPresent address: Electrophysiology Unit, Axxam S.P.A., Via Meucci 3, Bresso, 20091, Milan, ItalyThese authors contributed equally: Andrea Balboni and Camilla D’Angelo.Authors and AffiliationsExperimental Imaging Centre, San Raffaele Scientific Institute IRCCS, 20132, Milan, ItalyAndrea Balboni, Camilla D’Angelo, Nicoletta Collura, Altea Targa, Beatrice Massoti & Andrea MenegonDivision of Neuroscience, San Raffaele Scientific Institute IRCCS, 20132, Milan, ItalySimone Brusco, Claudia Di Berardino & Vania BroccoliCNR-Institute of Biophysics, Milan, ItalyEloise Mastrangelo & Mario MilaniChemistry Department, Milan University, 20133, Milan, ItalyPierfausto SeneciCNR-Institute of Neuroscience, Milan, ItalyVania BroccoliINsPE, San Raffaele Scientific Institute IRCCS, 20132, Milan, ItalyLuca MuzioNeural Stem Cell Biology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, ItalyRossella GalliAuthorsAndrea BalboniView author publicationsYou can also search for this author in.

下载参考文献致谢我们感谢Dey Sumit Kumar博士在LVs生产中提供的技术援助。作者信息作者notesSimone BruscoPresent地址：Axxam S.P.A.电生理科，Via Meucci 3，Bresso，20091，Milan，Italy这些作者做出了同样的贡献：Andrea Balboni和Camilla D'Angelo。作者和附属机构圣拉斐尔科学研究所实验成像中心IRCCS，20132，米兰，意大利安德烈亚·巴尔博尼，卡米拉·德安杰洛，尼古莱塔·科拉拉，阿尔塔·塔加，比阿特丽斯·马索蒂和安德烈亚·梅内戈迪维辛神经科学，圣拉斐尔科学研究所IRCCS，20132，米兰，意大利布鲁斯科，克劳迪亚·迪贝拉迪诺和瓦尼亚·布罗科利纳生物物理研究所，米兰，意大利伊莱·马斯特兰格罗和马里奥·米兰化学系，20133，米兰，意大利皮耶尔福斯托·塞内奇纳神经科学研究所，米兰，意大利Lyvania BroccoliINsPE，圣拉斐尔科学研究所IRCCS，20132，米兰，IRCCS圣拉斐尔科学研究所神经科学系ItalyLuca MuzioNeural干细胞生物学单位，米兰，ItalyRossella GalliauthorsandreaBalboniview作者出版物你也可以在中搜索这位作者。

PubMed Google ScholarCamilla D’AngeloView author publicationsYou can also search for this author in

PubMed Google ScholarCamilla D'AngeloView作者出版物您也可以在

PubMed Google ScholarNicoletta ColluraView author publicationsYou can also search for this author in

PubMed Google ScholarNicoletta ColluraView作者出版物您也可以在

PubMed Google ScholarSimone BruscoView author publicationsYou can also search for this author in

PubMed Google ScholarSimone BruscoView作者出版物您也可以在

PubMed Google ScholarClaudia Di BerardinoView author publicationsYou can also search for this author in

PubMed Google ScholarClaudia Di BerardinoView作者出版物您也可以在

PubMed Google ScholarAltea TargaView author publicationsYou can also search for this author in

PubMed Google ScholarAltea TargaView作者出版物您也可以在

PubMed Google ScholarBeatrice MassotiView author publicationsYou can also search for this author in

PubMed Google ScholarBeatrice MassotiView作者出版物您也可以在

PubMed Google ScholarEloise MastrangeloView author publicationsYou can also search for this author in

PubMed Google ScholarEloise MastrangeloView作者出版物您也可以在

PubMed Google ScholarMario MilaniView author publicationsYou can also search for this author in

PubMed Google ScholarMario MilaniView作者出版物您也可以在

PubMed Google ScholarPierfausto SeneciView author publicationsYou can also search for this author in

PubMed Google ScholarPierfausto SeneciView作者出版物您也可以在

PubMed Google ScholarVania BroccoliView author publicationsYou can also search for this author in

PubMed Google ScholarVania BroccoliView作者出版物您也可以在

PubMed Google ScholarLuca MuzioView author publicationsYou can also search for this author in

PubMed Google ScholarLuca MuzioView作者出版物您也可以在

PubMed Google ScholarRossella GalliView author publicationsYou can also search for this author in

PubMed Google ScholarRossella GalliView作者出版物您也可以在

PubMed Google ScholarAndrea MenegonView author publicationsYou can also search for this author in

PubMed谷歌学术评论MenegonView作者出版物您也可以在

PubMed Google ScholarContributionsA.B., C.D. and N.C. contributed to experimental design, performed pharmacological experiments and analysed data. C.D. performed Immunofluorescence and Cell Cycle studies. S.B. and C.DB. performed Electrophysiological experiments; A.T. designed and generated shRNAs encoding LVs; B.M.

。B、，C.D.和N.C.为实验设计做出了贡献，进行了药理实验并分析了数据。C、 D.进行免疫荧光和细胞周期研究。S、 B.和C.DB。进行电生理实验；A、 T.设计和产生编码LV的shRNA；B、 M。

performed immunoblotting experiments; E.M. and M.M. performed in silico studies; P.S. revised the manuscript and performed in silico studies. V.B. revised the manuscript, L.M. performed neuronal cultures, helped with virus design and revised the manuscript; R.G. provided biological samples and gave assistance in GBM culture.

进行了免疫印迹实验；E、 M.和M.M.进行了计算机研究；P、美国修订了手稿并进行了计算机研究。五、；R、 G.提供生物样品并协助GBM培养。

A.M. conceived the aim, led the project, wrote the paper and provided funding to complete the research. All authors reviewed, contributed to, and approved the final version.Corresponding authorCorrespondence to.

A、 M.构思了目标，领导了该项目，撰写了论文并提供了资金来完成研究。所有作者都审查，贡献并批准了最终版本。对应作者对应。

Andrea Menegon.Ethics declarations

安德烈梅内贡。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

。

Ethical approval

道德认可

GBM specimens used for molecular analysis and stem cell establishment were collected from patients with histologic diagnosis of primary GBM (WHO grade 4 glioma) after informed consent was obtained from all subjects and/or their legal guardian(s). The experimentation has been performed following the ethical standards of Declaration of Helsinki and in accordance with the protocol 01-CSC07 approved by the institutional ethical review board of San Raffaele Scientific Institute to R.G.

在获得所有受试者和/或其法定监护人的知情同意后，从组织学诊断为原发性GBM（WHO 4级神经胶质瘤）的患者中收集用于分子分析和干细胞建立的GBM标本。实验是按照赫尔辛基宣言的道德标准进行的，并根据圣拉斐尔科学研究所机构伦理审查委员会批准的方案01-CSC07进行的。

Cortical neurons were prepared from C57BL6J mice that were maintained under pathogen-free conditions at San Raffaele Hospital mouse facility (Milan, Italy). Mice were used in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) and with the ARRIVE guidelines. The Ethics Review Committee approved experimental protocols according guidelines from the Italian Ministry of Health and from the Institutional Animal Care and Use Committee of the San Raffaele Scientific Institute (protocol number 372/2021-PR)..

皮质神经元由C57BL6J小鼠制备，该小鼠在圣拉斐尔医院小鼠设施（意大利米兰）的无病原体条件下维持。根据1986年11月24日欧洲共同体理事会指令（86/609/EEC）和ARRIVE指南使用小鼠。伦理审查委员会根据意大利卫生部和圣拉斐尔科学研究所机构动物护理和使用委员会的指导方针批准了实验方案（方案编号372/2021-PR）。。

Additional informationPublisher's noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary InformationSupplementary Figures.Rights and permissions

。补充信息补充数字。权限和权限

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 you modified the licensed material.

开放获取本文是根据知识共享署名非商业性NoDerivatives 4.0国际许可证授权的，该许可证允许以任何媒介或格式进行任何非商业性使用，共享，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，并指出您是否修改了许可材料。

You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by-nc-nd/4.0/..

Reprints and permissionsAbout this articleCite this articleBalboni, A., D’Angelo, C., Collura, N. et al. Acid-sensing ion channel 3 is a new potential therapeutic target for the control of glioblastoma cancer stem cells growth.

转载和许可本文引用本文Balboni，A.，D'Angelo，C.，Collura，N。等人。酸敏感离子通道3是控制胶质母细胞瘤癌症干细胞生长的新潜在治疗靶标。

Sci Rep 14, 20421 (2024). https://doi.org/10.1038/s41598-024-71623-9Download citationReceived: 02 February 2024Accepted: 29 August 2024Published: 03 September 2024DOI: https://doi.org/10.1038/s41598-024-71623-9Share 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1420421（2024）。https://doi.org/10.1038/s41598-024-71623-9Download引文接收日期：2024年2月2日接受日期：2024年8月29日发布日期：2024年9月3日OI：https://doi.org/10.1038/s41598-024-71623-9Share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。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供

CommentsBy submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

评论通过提交评论，您同意遵守我们的条款和社区指南。如果您发现有虐待行为或不符合我们的条款或准则，请将其标记为不合适。

全球产业链接平台

重庆市渝北区金星科技大厦A区5楼512室

联系电话：023-67139735（重庆）

关于我们

产品服务