• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

RNA mA 甲基化通过 FOXO3 介导的自噬调节肝癌对索拉非尼的耐药性。

RNA m A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy.

机构信息

Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.

出版信息

EMBO J. 2020 Jun 17;39(12):e103181. doi: 10.15252/embj.2019103181. Epub 2020 May 5.

DOI:10.15252/embj.2019103181
PMID:32368828
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7298296/
Abstract

N6-methyladenosine (m A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m A methyltransferase, is significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy-associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m A modification of the FOXO3 mRNA 3'-untranslated region increasing its stability through a YTHDF1-dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m A-dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3-mediated m A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m A modification in the resistance of HCC to sorafenib therapy.

摘要

N6-甲基腺苷（m A）是 mRNA 中一种丰富的核苷酸修饰，已知其可调节 mRNA 的稳定性、剪接和翻译，但它是否在肿瘤内微环境和癌症药物耐药性中也具有生理作用尚不清楚。在这里，我们发现 METTL3，一种主要的 m A 甲基转移酶，在人索拉非尼耐药性肝癌（HCC）中显著下调。在低氧条件下耗尽 METTL3 会促进培养的 HCC 细胞中的索拉非尼耐药性和血管生成基因的表达，并激活自噬相关途径。在机制上，我们已经确定 FOXO3 是 METTL3 的关键下游靶标，METTL3 通过 YTHDF1 依赖性机制修饰 FOXO3 mRNA 3'非翻译区，增加其稳定性。对临床样本的分析进一步表明，METTL3 和 FOXO3 水平在 HCC 患者中紧密相关。在小鼠异种移植模型中，通过消除鉴定的 METTL3 介导的 FOXO3 mRNA 稳定化，耗尽 METTL3 会显著增强 HCC 对索拉非尼的耐药性，而过表达 FOXO3 则恢复 m A 依赖性索拉非尼敏感性。总之，我们的工作揭示了 METTL3 介导的 m A 修饰在缺氧肿瘤微环境中的关键功能，并确定 FOXO3 是 HCC 对索拉非尼治疗耐药性中 m A 修饰的重要靶标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/b57ab64d31dd/EMBJ-39-e103181-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/233e49522600/EMBJ-39-e103181-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/30adb20cb97d/EMBJ-39-e103181-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/575560a20aee/EMBJ-39-e103181-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/9b7099356e2d/EMBJ-39-e103181-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/ee94a3345608/EMBJ-39-e103181-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/6c139bbef82f/EMBJ-39-e103181-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/b57ab64d31dd/EMBJ-39-e103181-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/233e49522600/EMBJ-39-e103181-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/30adb20cb97d/EMBJ-39-e103181-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/575560a20aee/EMBJ-39-e103181-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/9b7099356e2d/EMBJ-39-e103181-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/ee94a3345608/EMBJ-39-e103181-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/6c139bbef82f/EMBJ-39-e103181-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b338/7298296/b57ab64d31dd/EMBJ-39-e103181-g008.jpg

相似文献

1
RNA m A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy.RNA mA 甲基化通过 FOXO3 介导的自噬调节肝癌对索拉非尼的耐药性。
EMBO J. 2020 Jun 17;39(12):e103181. doi: 10.15252/embj.2019103181. Epub 2020 May 5.
2
Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib.自噬相关的化学保护作用抵抗索拉非尼在人肝癌：FOXO3 上调的作用和雷戈非尼的调节。
Int J Mol Sci. 2021 Oct 29;22(21):11770. doi: 10.3390/ijms222111770.
3
m6A RNA methylation-mediated HNF3γ reduction renders hepatocellular carcinoma dedifferentiation and sorafenib resistance.m6A RNA 甲基化介导的 HNF3γ 减少导致肝细胞癌去分化和索拉非尼耐药。
Signal Transduct Target Ther. 2020 Dec 26;5(1):296. doi: 10.1038/s41392-020-00299-0.
4
CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1.环状 RNA-SORE 通过稳定 YBX1 介导肝癌对索拉非尼的耐药性。
Signal Transduct Target Ther. 2020 Dec 26;5(1):298. doi: 10.1038/s41392-020-00375-5.
5
Long intergenic non-protein coding RNA 1273 confers sorafenib resistance in hepatocellular carcinoma via regulation of methyltransferase 3.长链非编码 RNA 1273 通过调控甲基转移酶 3 赋予肝癌索拉非尼耐药性。
Bioengineered. 2022 Feb;13(2):3108-3121. doi: 10.1080/21655979.2022.2025701.
6
METTL3 and METTL14-mediated N-methyladenosine modification of SREBF2-AS1 facilitates hepatocellular carcinoma progression and sorafenib resistance through DNA demethylation of SREBF2.METTL3 和 METTL14 介导的 SREBF2-AS1 的 N6-甲基腺苷修饰通过 SREBF2 的 DNA 去甲基化促进肝细胞癌进展和索拉非尼耐药。
Sci Rep. 2024 Mar 14;14(1):6155. doi: 10.1038/s41598-024-55932-7.
7
Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma.缺氧通过激活 FOXO3a 在肝癌中诱导自噬介导的索拉非尼耐药。
Cell Death Dis. 2020 Nov 29;11(11):1017. doi: 10.1038/s41419-020-03233-y.
8
HBXIP drives metabolic reprogramming in hepatocellular carcinoma cells via METTL3-mediated m6A modification of HIF-1α.HBXIP 通过 METTL3 介导的 HIF-1α m6A 修饰驱动肝癌细胞的代谢重编程。
J Cell Physiol. 2021 May;236(5):3863-3880. doi: 10.1002/jcp.30128. Epub 2020 Dec 11.
9
SOX9 enhances sorafenib resistance through upregulating ABCG2 expression in hepatocellular carcinoma.SOX9 通过上调 ABCG2 表达增强肝癌对索拉非尼的耐药性。
Biomed Pharmacother. 2020 Sep;129:110315. doi: 10.1016/j.biopha.2020.110315. Epub 2020 Jun 15.
10
PRMT6 deficiency induces autophagy in hostile microenvironments of hepatocellular carcinoma tumors by regulating BAG5-associated HSC70 stability.PRMT6 缺乏通过调节 BAG5 相关的 HSC70 稳定性诱导肝癌肿瘤恶劣微环境中的自噬。
Cancer Lett. 2021 Mar 31;501:247-262. doi: 10.1016/j.canlet.2020.11.002. Epub 2020 Nov 11.

引用本文的文献

1
Small-molecule and peptide inhibitors of m6A regulators.m6A调控因子的小分子和肽类抑制剂
Front Oncol. 2025 Aug 1;15:1629864. doi: 10.3389/fonc.2025.1629864. eCollection 2025.
2
Forkhead box O proteins in chondrocyte aging and diseases.软骨细胞衰老和疾病中的叉头框O蛋白
J Orthop Translat. 2025 Aug 10;54:167-179. doi: 10.1016/j.jot.2025.07.011. eCollection 2025 Sep.
3
Targeting m6A methylation for early diagnosis and precision medicine in hepatocellular carcinoma.靶向m6A甲基化用于肝细胞癌的早期诊断和精准医学

本文引用的文献

1
Reading, writing and erasing mRNA methylation.阅读、书写和擦除 mRNA 甲基化。
Nat Rev Mol Cell Biol. 2019 Oct;20(10):608-624. doi: 10.1038/s41580-019-0168-5. Epub 2019 Sep 13.
2
A global view of hepatocellular carcinoma: trends, risk, prevention and management.全球视角下的肝细胞癌：趋势、风险、预防与管理。
Nat Rev Gastroenterol Hepatol. 2019 Oct;16(10):589-604. doi: 10.1038/s41575-019-0186-y. Epub 2019 Aug 22.
3
Hepatocellular Carcinoma.肝细胞癌
Cancer Cell Int. 2025 Jul 28;25(1):286. doi: 10.1186/s12935-025-03923-7.
4
Exploring the Molecular Mechanism of 1,25(OH)D Reversal of Sorafenib Resistance in Hepatocellular Carcinoma Based on Network Pharmacology and Experimental Validation.基于网络药理学和实验验证探索1,25(OH)D逆转肝癌中索拉非尼耐药的分子机制
Curr Issues Mol Biol. 2025 Apr 29;47(5):319. doi: 10.3390/cimb47050319.
5
Emerging Concepts in Immuno-Oncology: Insights from Natural Language Processing-Driven Co-Occurrence Analysis.免疫肿瘤学中的新兴概念：来自自然语言处理驱动的共现分析的见解
ACS Omega. 2025 Jun 27;10(27):28587-28614. doi: 10.1021/acsomega.5c00693. eCollection 2025 Jul 15.
6
Targeting epigenetic regulators as a promising avenue to overcome cancer therapy resistance.将表观遗传调节因子作为克服癌症治疗耐药性的一条有前景的途径。
Signal Transduct Target Ther. 2025 Jul 18;10(1):219. doi: 10.1038/s41392-025-02266-z.
7
Emerging mechanisms and implications of m6A in CVDs: potential applications of natural products.m6A在心血管疾病中的新兴机制及意义：天然产物的潜在应用
Front Cardiovasc Med. 2025 Jun 30;12:1559064. doi: 10.3389/fcvm.2025.1559064. eCollection 2025.
8
Autophagy in orthodontic tooth movement: advances, challenges, and future perspectives.正畸牙齿移动中的自噬：进展、挑战及未来展望。
Mol Med. 2025 Jun 21;31(1):245. doi: 10.1186/s10020-025-01299-y.
9
N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism.N6-甲基腺苷修饰的GPX2通过调节氧化还原代谢影响癌细胞干性和对酪氨酸激酶抑制剂的耐药性。
Cell Death Dis. 2025 Jun 18;16(1):458. doi: 10.1038/s41419-025-07764-0.
10
RNA epigenetic modifications as dynamic biomarkers in cancer: from mechanisms to clinical translation.RNA表观遗传修饰作为癌症中的动态生物标志物：从机制到临床转化
Biomark Res. 2025 Jun 7;13(1):81. doi: 10.1186/s40364-025-00794-y.
N Engl J Med. 2019 Apr 11;380(15):1450-1462. doi: 10.1056/NEJMra1713263.
4
RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3.RNA N6-甲基腺嘌呤去甲基化酶 FTO 通过抑制 BNIP3 促进乳腺癌进展。
Mol Cancer. 2019 Mar 28;18(1):46. doi: 10.1186/s12943-019-1004-4.
5
METTL3 and ALKBH5 oppositely regulate mA modification of mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes.METTL3 和 ALKBH5 对 mRNA 的 mA 修饰起相反调控作用，从而决定了低氧/复氧处理的心肌细胞的命运。
Autophagy. 2019 Aug;15(8):1419-1437. doi: 10.1080/15548627.2019.1586246. Epub 2019 Mar 17.
6
Cancer statistics, 2019.癌症统计数据，2019 年。
CA Cancer J Clin. 2019 Jan;69(1):7-34. doi: 10.3322/caac.21551. Epub 2019 Jan 8.
7
-Methyladenosine modification: a novel pharmacological target for anti-cancer drug development.N6-甲基腺苷修饰：抗癌药物研发的新型药理学靶点。
Acta Pharm Sin B. 2018 Oct;8(6):833-843. doi: 10.1016/j.apsb.2018.06.001. Epub 2018 Jun 6.
8
A dynamic N-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors.动态 N6-甲基腺苷甲基化组调控酪氨酸激酶抑制剂的内在和获得性耐药性。
Cell Res. 2018 Nov;28(11):1062-1076. doi: 10.1038/s41422-018-0097-4. Epub 2018 Oct 8.
9
Life, death and autophagy.生命、死亡与自噬。
Nat Cell Biol. 2018 Oct;20(10):1110-1117. doi: 10.1038/s41556-018-0201-5. Epub 2018 Sep 17.
10
FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis.FoxO 功能对于成体神经发生中的自噬通量和神经元形态发生的维持至关重要。
Neuron. 2018 Sep 19;99(6):1188-1203.e6. doi: 10.1016/j.neuron.2018.08.017. Epub 2018 Sep 6.