AbstractStudies have underscored the pivotal role of metastasis-associated protein 3 (MTA3) as a cancer regulator, yet its potential as a drug target across cancers necessitates comprehensive evaluation. In this study, we analyzed MTA3 expression profiles to ascertain its diagnostic and prognostic value in pan-cancers, probing associations with genetic variations and immunological characteristics.

摘要研究强调了转移相关蛋白3（MTA3）作为癌症调节剂的关键作用，但其作为癌症药物靶标的潜力需要全面评估。在这项研究中，我们分析了MTA3表达谱，以确定其在泛癌中的诊断和预后价值，探讨了与遗传变异和免疫学特征的关联。

Notably, liver hepatocellular carcinoma (LIHC) exhibited the most significant correlation with MTA3. By transfection of siRNA, interference of MTA3 affected HepG2 and Hepa1-6 cell viability and migration. Through drug screening and drug-likeness evaluation among marine-derived natural products, Jaspamycin was identified as a potential hepatocellular carcinoma treatment by targeting MTA3.

。通过转染siRNA，MTA3的干扰影响HepG2和Hepa1-6细胞的活力和迁移。通过对海洋衍生天然产物的药物筛选和药物相似性评估，茉莉霉素被确定为靶向MTA3的潜在肝细胞癌治疗药物。

By applying in vitro and in vivo experiment, the inhibitory effects of Jaspamycin on hepatocellular carcinoma viability, migration, and tumor progression were observed. To assess the potential of MTA3 as an anticancer drug target, MTA3 overexpression plasmid was transfected together with Jaspamycin treatment, and observed that MTA3 upregulation counteracted the inhibitory effects of Jaspamycin on hepatocarcinoma cell proliferation and migration, underscoring the efficacy of MTA3 as a drug target in hepatocellular carcinoma drug screening.

通过体外和体内实验，观察了茉莉霉素对肝细胞癌活力，迁移和肿瘤进展的抑制作用。为了评估MTA3作为抗癌药物靶标的潜力，将MTA3过表达质粒与茉莉霉素处理一起转染，并观察到MTA3上调抵消了茉莉霉素对肝癌细胞增殖和迁移的抑制作用，强调了MTA3作为药物靶标在肝细胞癌药物筛选中的作用。

This study highlights the clinical significance of MTA3 in pan-cancer, particularly in hepatocellular carcinoma. Additionally, it identifies Jaspamycin, a marine-derived compound with promising pharmacological properties, as an effective inhibitor of MTA3 activity, suggesting its potential for hepatocellular carcinoma treatment..

这项研究强调了MTA3在泛癌，特别是肝细胞癌中的临床意义。此外，它还确定了茉莉霉素（一种具有良好药理特性的海洋衍生化合物）是MTA3活性的有效抑制剂，表明其具有治疗肝细胞癌的潜力。。

IntroductionMarine-derived natural products have garnered significant attention within the medical community due to their distinct chemical structures and biological activities. Over recent decades, scientists have unearthed numerous bioactive molecules from oceanic sources, unveiling their potential roles in cancer therapy and opening up new avenues for cancer treatment.

引言海洋衍生天然产物由于其独特的化学结构和生物活性而在医学界引起了极大的关注。。

For instance, Plocabulin, extracted from the sponge Lithoplocamia lithistoides, is presently undergoing phase II clinical trials for the treatment of advanced solid tumors1. Marine natural products are believed to possess heightened bioactivity and bioavailability, presenting immense potential for the discovery of novel anticancer drugs2,3.

。海洋天然产物被认为具有较高的生物活性和生物利用度，为发现新型抗癌药物提供了巨大潜力2,3。

However, the translation of marine-derived natural products into clinically applicable anticancer drugs encounters several challenges, including the screening of natural products, assessment of biological activity, pharmacological investigation, among others challenges. Consequently, advancing research in the drug screening of marine-derived natural products necessitates interdisciplinary collaboration and innovative technical approaches to effectively address these challenges.Cancer poses a substantial global health burden, with statistics showing that cancer-related fatalities accounted for one-sixth of all global deaths by 20204.

然而，将海洋衍生的天然产物转化为临床适用的抗癌药物遇到了一些挑战，包括天然产物的筛选，生物活性的评估，药理学研究等挑战。因此，推进海洋衍生天然产物药物筛选的研究需要跨学科合作和创新的技术方法来有效应对这些挑战。癌症对全球健康构成了巨大负担，统计数据显示，到20204年，与癌症相关的死亡人数占全球死亡人数的六分之一。

Pan-cancer analysis provides a unique perspective in cancer research, facilitating the thorough examination of shared characteristics and variations in molecular profiles and biological mechanisms across diverse cancer types5. This approach is instrumental in augmenting our comprehensive comprehension of cancer, identifying potential therapeutic targets, and enhancing early cancer detection and treatment strategies.

泛癌分析为癌症研究提供了独特的视角，有助于彻底检查不同癌症类型的分子谱和生物学机制的共同特征和变异5。这种方法有助于增强我们对癌症的全面理解，确定潜在的治疗靶点，并增强早期癌症检测和治疗策略。

In essence, pan-cance.

从本质上讲，泛癌。

NC-siRNA: 5′-UUCUCCGAACGUGUCACGUTT-3′.

NC-SIRNA：5′-uucuccgaacgutt-3′。

MTA3-siRNA: 5′-GUGCAACAGAAACGUCUAATT-3′.

MTA3 siRNA：5′-谷氨酸-谷氨酸-3′。

Real-time PCRTotal RNA was harvested from cells using TRIzol reagent (Invitrogen, US) according to the manufacturer’s protocols. cDNA synthesis was performed using a High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Carlsbad, CA, USA). The levels of mRNAs were determined by SYBR green I incorporation method and real-time PCR system (ABI7500, Applied Biosystems, Carlsbad, CA, USA).

根据制造商的规程，使用TRIzol试剂（Invitrogen，US）从细胞中收获实时PCRTotal RNA。使用高容量cDNA逆转录试剂盒（Applied Biosystems，Carlsbad，CA，USA）进行cDNA合成。通过SYBR green I掺入法和实时PCR系统（ABI7500，Applied Biosystems，Carlsbad，CA，USA）测定mRNA的水平。

All results were processed with GAPDH for standardization. Relative mRNA levels were calculated by 2−ΔΔCq. The primer sequences used were:.

所有结果均使用GAPDH进行标准化处理。通过2-ΔΔCq计算相对mRNA水平。使用的引物序列是：。

MTA3: Forward: 5′-AGCCCACTTACGGATCGACAGA-3′.

MTA3: Forward: 5′-AGCCCACTTACGGATCGACAGA-3′.

Reverse: 5′-CAAACTAGGCTGCCTCACAGAAC-3′.

反向：5′-CAACATAGGCTGCCTCAGAAC-3′。

GAPDH: Forward: 5′-GCCCAATACGACCAAATCC-3′.

GAPDH: Forward: 5′-GCCCAATACGACCAAATCC-3′.

Reverse: 5′-CTCTGCTCCTCCTGTTCGAC-3′.

反向：5'-CTCTGCTCCTCTGTTCGAC-3'。

The reaction conditions were as follows: 45 cycles, 95 °C: pre-change for 15 s, 95 °C: denaturation for 5 s, 60 °C: annealing and extension for 30 s.Cell number assessmentTo evaluate cell viability, the Cell Counting Kit-8 (CCK8, Solarbio, China) was used. For the CCK8 assay, 10 µL of CCK8 solution was added to HepG2 and Hepa1-6 in a 96-well plate, followed by a 4-hour incubation period.

反应条件如下：45个循环，95°C：预变化15 s，95°C：变性5 s，60°C：退火和延伸30 s。细胞数量评估为了评估细胞活力，使用细胞计数试剂盒-8（CCK8，Solarbio，China）。对于CCK8测定，将10μlCCK8溶液加入96孔板中的HepG2和Hepa1-6中，然后进行4小时的孵育期。

The absorbance was then measured at 450 nm.Wound healing testCells were inoculated in 6-well plates and allowed to grow until they reached 85% confluence, a 200 µL pipette tip was used to create a scratch in the cell monolayer. The cell surface was gently rinsed once with serum-free medium to remove cell debris.

。伤口愈合试验将细胞接种在6孔板中并使其生长直至达到85%汇合，使用200μL移液管尖端在细胞单层中产生划痕。用无血清培养基轻轻冲洗细胞表面一次以除去细胞碎片。

The cells were then observed and imaged under a microscope (Nikon, Melville, NY, USA). Afterward, the cells were incubated at 37 °C with 5% CO2 for 48 h, photographed again, and the migration rate of each group was calculated.$$\mathrm{Migration}\;\mathrm{rate}\;(\%)\:=\:\mathrm{scratch}\;\mathrm{distance}\;(\mathrm{initial}\;\mathrm{time})\;-\;\mathrm{scratch}\;\mathrm{distance}\;(\mathrm{after}\;48\;\mathrm{hours})/\;\mathrm{scratch}\;\mathrm{distance}\;(\mathrm{initial}\;\mathrm{time})\;\times100.$$Transwell migration and invasion assayA 200 uL of cell suspension containing 1 × 105cells/mL was inoculated into Transwell chambers (8 μm pore size, Corning, New York, NY, USA), while 800 µL of culture medium with 10% FBS was added to the lower chamber.

然后观察细胞并在显微镜下成像（尼康，梅尔维尔，纽约，美国）。然后，将细胞在37℃，5%CO 2下孵育48小时，再次拍照，并计算每组的迁移率$$\数学{迁移}\；\数学{速率}\；（\%）\：=\：\数学{划痕}\；\数学{距离}\；（\mathrm{initial}\；\mathrm{time}）\；-\；\数学{划痕}\；\数学{距离}\；（\mathrm{之后}\；48 \；\mathrm{小时}）/\；\数学{划痕}\；\数学{距离}\；（\mathrm{initial}\；\mathrm{time}）\；\times100。$$Transwell迁移和侵袭测定将200μL含有1×105个细胞/mL的细胞悬液接种到Transwell室（孔径8μm，Corning，New York，NY，USA）中，同时将800μL含有10%FBS的培养基加入下室。

After 48 h of incubation, non-migrated cells on the upper surface of the membrane were removed with a cotton swab. The migrated cells were stained with 0.1% crystal violet for 30 min, visualized, and counted under a microscope (Nikon, Melville, NY, USA) at 200× magnification.Computer-aided drug design approachesMolecular docking was.

孵育48小时后，用棉签除去膜上表面的未迁移细胞。将迁移的细胞用0.1%结晶紫染色30分钟，可视化，并在显微镜（Nikon，Melville，NY，USA）下以200倍放大率计数。计算机辅助药物设计方法分子对接是。

Data availability

数据可用性

The simulation experiment data used to support the findings of this study are available from the corresponding author upon request.

用于支持本研究结果的模拟实验数据可应要求从通讯作者处获得。

AbbreviationsACC:

缩写ACC：

Adrenocortical carcinoma

BLCA:

BLCA：

Bladder Urothelial Carcinoma

膀胱尿路上皮癌

BRCA:

BRCA：

Breast invasive carcinoma

乳腺浸润癌

CESC:

CESC：

Cervical squamous cell carcinoma and endocervical adenocarcinoma

宫颈鳞状细胞癌和宫颈腺癌

CHOL:

乔尔：

Cholangiocarcinoma

胆管癌

COAD:

COAD：

Colon adenocarcinoma

结肠腺癌

COADREAD:

coadare：

Colon adenocarcinoma/Rectum adenocarcinoma Esophageal carcinoma

结肠腺癌/直肠腺癌食管癌

DLBC:

DLBC：

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma

淋巴肿瘤弥漫性大B细胞淋巴瘤

ESCA:

ESCA：

Esophageal carcinoma

食管癌

FPPP:

FPPP：

FFPE Pilot Phase II

FFPE试点二期

GBM:

GBM：

Glioblastoma multiforma

多形性胶质母细胞瘤

GBMLGG:

GBMLGG：

Glioma

神经胶质瘤

HNSC:

HNSC：

Head and Neck squamous cell carcinoma

头颈部鳞状细胞癌

KICH:

基奇：

Kidney Chromophobe

肾嫌色细胞

KIPAN:

基潘：

Pan-kidney cohort

泛肾队列

KIRC:

柯克：

Kidney renal clear cell carcinoma

肾透明细胞癌

KIRP:

唧唧：

Kidney renal papillary cell carcinoma

肾乳头状细胞癌

LAML:

拉姆尔：

Acute Myeloid Leukemia

急性骨髓性白血病

LGG:

LGG：

Brain Lower Grade Glioma

脑低级别胶质瘤

LIHC:

LIHC公司：

Liver hepatocellular carcinoma

肝细胞肝癌

LUAD:

鲁德：

Lung adenocarcinoma

肺腺癌

LUSC:

LUSC：

Lung squamous cell carcinoma

肺鳞状细胞癌

MESO:

中观：

Mesothelioma

间皮瘤

OV:

OV：

Ovarian serous cystadenocarcinoma

卵巢浆液性囊腺癌

PAAD:

路径：

Pancreatic adenocarcinoma

胰腺癌

PCPG:

PCPG：

Pheochromocytoma and Paraganglioma

嗜铬细胞瘤和副神经节瘤

PRAD:

PRAD：

Prostate adenocarcinoma

前列腺腺癌

READ:

阅读：

Rectum adenocarcinoma

直肠腺癌

SARC:

SARC公司：

Sarcoma

肉瘤

STAD:

STAD：

Stomach adenocarcinoma

胃腺癌

SKCM:

SKCM：

Skin Cutaneous Melanoma

皮肤黑色素瘤

STES:

STES：

Stomach and Esophageal carcinoma

胃和食管癌

TGCT:

TGCT：

Testicular Germ Cell Tumors

睾丸生殖细胞肿瘤

THCA:

THCA：

Thyroid carcinoma

甲状腺癌

THYM:

百里香：

Thymoma

胸腺瘤

UCEC:

UCEC：

Uterine Corpus Endometrial Carcinoma

子宫体子宫内膜癌

UCS:

UCS：

Uterine Carcinosarcoma

子宫癌肉瘤

UVM:

UVM:

Uveal Melanoma

葡萄膜黑色素瘤

OS:

操作系统：

Osteosarcoma

骨肉瘤

ALL:

全部：

Acute Lymphoblastic Leukemia

急性淋巴细胞白血病

NB:

注意：

Neuroblastoma

神经母细胞瘤

WT:

重量：

High-Risk Wilms Tumor

高危肾母细胞瘤

MTA3:

MTA3：

Metastasis-associated protein 3

转移相关蛋白3

CADD:

球童：

Computer-aided drug design

计算机辅助药物设计

OS:

操作系统：

Overall survival

总体生存率

DSS:

Disease-specific survival

疾病特异性生存

DFI:

DFI：

Disease-free interval

无病间隔

PFI:

PFI：

Progression-free interval

无进展间隔

TIICs:

TICS：

Infiltrating immune cells

浸润免疫细胞

DEGs:

学位：

Differentially expressed genes

差异表达基因

MSI:

MSI（微星）：

Microsatellite instability

微卫星不稳定性

AFP:

法新社：

Alpha-fetoprotein

甲胎蛋白

siMTA3:

siMTA3：

MTA3 small interfering RNA

MTA3小干扰RNA

NC:

北卡罗来纳州：

Negative control (NC)

阴性对照（NC）

CCK8:

CCK8：

Cell Counting Kit-8

细胞计数试剂盒-8

ADMET:

ADMET：

Absorption, distribution, metabolism, excretion, and toxicity

吸收，分布，代谢，排泄和毒性

TME:

TME：

Tumor microenvironment

肿瘤微环境

PTX-2:

PTX-2:

Pectenotoxin-2

果胶毒素-2

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Heilongjiang Province Ordinary University Youth Innovation Talent Cultivation (UNPYSCT-2020159).Author informationAuthors and AffiliationsGraduate School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150001, ChinaYihan LiuMedical Technology Department, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, ChinaTong LuNational and Local Joint Engineering Laboratory for Synthesis Transformation and Separation of Extreme Environmental Nutrients, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, ChinaRunze Li & Dan XiaoCancer Hospital, Shenzhen Hospital, National Cancer Center, National Clinical Research Center for Cancer, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, Guangdong, ChinaRui XuSchool of Life Sciences, Faculty of Ecotechnologies, ITMO University, St.

黑龙江省普通高校青年创新人才培养（UNPYSCT-2020159）。作者信息作者和所属机构黑龙江中医药大学研究生院，黑龙江哈尔滨，150001，齐齐哈尔医科大学刘一汉医学技术系，黑龙江齐齐哈尔，161006，中国医学科学院和北京协和医学院，哈尔滨工业大学，哈尔滨，黑龙江，150001，哈尔滨工业大学，中国润泽李丹小肿瘤医院，深圳医院，国家癌症中心，国家癌症临床研究中心，中国医学科学院和北京协和医科大学，深圳，518116，广东，中国瑞许生命科学院，ITMO大学生态技术学院，圣。

Petersburg, 197101, RussiaDenis BaranenkoHeilongjiang Nursing Collage, Harbin, Heilongjiang, 150086, ChinaLida YangZhengzhou Research Institute, Harbin Institute of Technology, Zhengzhou, Henan, 450007, ChinaDan XiaoSchool of Medicine and Health, Harbin Institute of Technology, No. 92, Xidazhi Street, Nangang District, Harbin, 150001, Heilongjiang, ChinaDan XiaoAuthorsYihan LiuView author publicationsYou can also search for this author in.

Petersburg，197101，RussiaDenis BaranenkoHeilongjiang护理学院，黑龙江哈尔滨，150086，中国利达杨正洲研究所，哈尔滨工业大学，河南郑州，450007，中国哈尔滨工业大学医学与健康学院，哈尔滨市南岗区西大直街92号，黑龙江150001，中国小丹作者刘一汉观点作者出版物你也可以在中搜索这位作者。

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PubMed Google ScholarContributionsConceptualization, D.X. and Y.L.; methodology, Y.L.; software, Y.L.; validation, R.L.; in vitro experiments, D.X., Y.L., and R.L.; in vivo experiments, T.L., R.X., D.B., and D.Y.; writing-original draft preparation, D.X.; visualization, Y.L.; supervision, R.L.; funding acquisition, D.X.

PubMed谷歌学术贡献概念化，D.X.和Y.L。；方法论，Y.L。；软件，Y.L。；验证，R.L。；体外实验，D.X.，Y.L。和R.L。；体内实验，T.L.，R.X.，D.B。和D.Y。；撰写原稿准备，D.X。；可视化，Y.L。；监督，R.L。；资金收购，D.X。

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Reprints and permissionsAbout this articleCite this articleLiu, Y., Lu, T., Li, R. et al. Discovery of Jaspamycin from marine-derived natural product based on MTA3 to inhibit hepatocellular carcinoma progression.

转载和许可本文引用本文Liu，Y.，Lu，T.，Li，R。等人从基于MTA3的海洋衍生天然产物中发现了茉莉霉素，以抑制肝细胞癌的进展。

Sci Rep 14, 25294 (2024). https://doi.org/10.1038/s41598-024-75205-7Download citationReceived: 19 March 2024Accepted: 03 October 2024Published: 25 October 2024DOI: https://doi.org/10.1038/s41598-024-75205-7Share 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.

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KeywordsMTA3Pan-cancerHepatocellular carcinomaMarine-derived anticancer agentJaspamycin

关键词MTA3pan癌症肝细胞癌马林衍生的抗癌剂jaspamycin