• 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

FBP1 缺失通过肝星状细胞衰老分泌组破坏肝脏代谢并促进肿瘤发生。

FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome.

机构信息

Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

出版信息

Nat Cell Biol. 2020 Jun;22(6):728-739. doi: 10.1038/s41556-020-0511-2. Epub 2020 May 4.

DOI:10.1038/s41556-020-0511-2
PMID:32367049
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7286794/
Abstract

The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth.

摘要

肝细胞代谢失调与肿瘤微环境细胞之间的串扰，以及由此对肝肿瘤发生的影响，目前尚不完全清楚。我们在这里表明，肝实质细胞特异性缺失糖异生酶果糖 1,6-二磷酸酶 1（FBP1）会破坏肝脏代谢稳态并促进肿瘤进展。FBP1 在人类和鼠类肝肿瘤中普遍沉默。肝实质细胞特异性 Fbp1 缺失导致脂肪变性，同时激活和衰老肝星状细胞（HSCs），表现出衰老相关分泌表型。用达沙替尼/槲皮素或 ABT-263 进行“衰老细胞清除”治疗来耗尽衰老的 HSCs 可抑制肿瘤进展。我们进一步证明，FBP1 缺陷的肝细胞通过释放高迁移率族蛋白 B1（HMGB1）促进 HSC 激活；用小分子 inflachromene 阻断其释放可限制 FBP1 依赖性 HSC 激活、随后的衰老相关分泌表型的发展和肿瘤进展。总的来说，这些发现为 FBP1 作为肝癌中的代谢肿瘤抑制因子提供了遗传证据，并确立了肝细胞代谢与 HSC 衰老之间的关键串扰，促进了肿瘤生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/2368f291e0b5/nihms-1579974-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/5175ff612892/nihms-1579974-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/329438b09fb1/nihms-1579974-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/3b16466fb0d5/nihms-1579974-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/37e89453fb1b/nihms-1579974-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/d88f1d392c34/nihms-1579974-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/4d3f327c7130/nihms-1579974-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/8ce32928f8a3/nihms-1579974-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/216f0591d1a0/nihms-1579974-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/326e6e103e19/nihms-1579974-f0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/37b7c2a4fc62/nihms-1579974-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/66a1e0efa2d1/nihms-1579974-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/b66326dda9ea/nihms-1579974-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/92a90615de50/nihms-1579974-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/9f0e3516a0e5/nihms-1579974-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/79b3a135ea70/nihms-1579974-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/2368f291e0b5/nihms-1579974-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/5175ff612892/nihms-1579974-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/329438b09fb1/nihms-1579974-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/3b16466fb0d5/nihms-1579974-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/37e89453fb1b/nihms-1579974-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/d88f1d392c34/nihms-1579974-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/4d3f327c7130/nihms-1579974-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/8ce32928f8a3/nihms-1579974-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/216f0591d1a0/nihms-1579974-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/326e6e103e19/nihms-1579974-f0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/37b7c2a4fc62/nihms-1579974-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/66a1e0efa2d1/nihms-1579974-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/b66326dda9ea/nihms-1579974-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/92a90615de50/nihms-1579974-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/9f0e3516a0e5/nihms-1579974-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/79b3a135ea70/nihms-1579974-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac40/7286794/2368f291e0b5/nihms-1579974-f0007.jpg

相似文献

1
FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome.FBP1 缺失通过肝星状细胞衰老分泌组破坏肝脏代谢并促进肿瘤发生。
Nat Cell Biol. 2020 Jun;22(6):728-739. doi: 10.1038/s41556-020-0511-2. Epub 2020 May 4.
2
Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma.果糖-1,6-二磷酸酶表达降低与肝癌中的葡萄糖代谢和肿瘤进展相关。
Cancer Res. 2016 Jun 1;76(11):3265-76. doi: 10.1158/0008-5472.CAN-15-2601. Epub 2016 Apr 6.
3
Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production.肝细胞癌中的肝星状细胞通过生长分化因子 15 的产生促进肿瘤生长。
Gastroenterology. 2021 Apr;160(5):1741-1754.e16. doi: 10.1053/j.gastro.2020.12.015. Epub 2020 Dec 17.
4
CTGF Mediates Tumor-Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression.CTGF 介导肝癌细胞与肝星状细胞之间的肿瘤-基质相互作用，加速 HCC 进展。
Cancer Res. 2018 Sep 1;78(17):4902-4914. doi: 10.1158/0008-5472.CAN-17-3844. Epub 2018 Jul 2.
5
Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis.肝星状细胞亚群在肝癌发生中的相反作用。
Nature. 2022 Oct;610(7931):356-365. doi: 10.1038/s41586-022-05289-6. Epub 2022 Oct 5.
6
Extracellular vesicle-mediated communication between hepatocytes and natural killer cells promotes hepatocellular tumorigenesis.细胞外囊泡介导的肝细胞与自然杀伤细胞之间的通讯促进了肝细胞肿瘤的发生。
Mol Ther. 2022 Feb 2;30(2):606-620. doi: 10.1016/j.ymthe.2021.07.015. Epub 2021 Oct 1.
7
Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma.Gasdermin D 介导的衰老肝星状细胞中 IL-33 的释放促进肥胖相关肝细胞癌。
Sci Immunol. 2022 Jun 24;7(72):eabl7209. doi: 10.1126/sciimmunol.abl7209.
8
P300 Acetyltransferase Mediates Stiffness-Induced Activation of Hepatic Stellate Cells Into Tumor-Promoting Myofibroblasts.P300 乙酰转移酶介导肝星状细胞硬度诱导激活为促肿瘤肌成纤维细胞。
Gastroenterology. 2018 Jun;154(8):2209-2221.e14. doi: 10.1053/j.gastro.2018.02.015. Epub 2018 Feb 15.
9
Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression.抑制组蛋白去乙酰化酶通过恢复 FBP1 表达来抑制葡萄糖代谢和肝癌生长。
Sci Rep. 2017 Mar 6;7:43864. doi: 10.1038/srep43864.
10
The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors.HMGB1-RAGE 轴调节自噬缺陷性肝肿瘤的生长。
Cell Death Dis. 2020 May 7;11(5):333. doi: 10.1038/s41419-020-2536-7.

引用本文的文献

1
Role of cellular senescence in hepatic diseases (Review).细胞衰老在肝脏疾病中的作用（综述）
Int J Mol Med. 2025 Nov;56(5). doi: 10.3892/ijmm.2025.5623. Epub 2025 Sep 5.
2
The Role of Senescence, its Therapeutic Relevance and Clinical Implications in the Tumor Microenvironment.衰老在肿瘤微环境中的作用、其治疗相关性及临床意义
Theranostics. 2025 Jul 28;15(16):8675-8703. doi: 10.7150/thno.112633. eCollection 2025.
3
α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.α-酮戊二酸决定了人类癌症中用于能量感知的AMPK蛋白合成。

本文引用的文献

1
Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis.果糖-1,6-二磷酸酶 2 通过抑制线粒体生物发生来抑制肉瘤进展。
Cell Metab. 2020 Jan 7;31(1):174-188.e7. doi: 10.1016/j.cmet.2019.10.012. Epub 2019 Nov 21.
2
Cellular Senescence: Defining a Path Forward.细胞衰老：定义前进的道路。
Cell. 2019 Oct 31;179(4):813-827. doi: 10.1016/j.cell.2019.10.005.
3
Inducing and exploiting vulnerabilities for the treatment of liver cancer.诱导和利用肝癌治疗中的脆弱性。
Nat Chem Biol. 2025 Aug 22. doi: 10.1038/s41589-025-02013-z.
4
Notoginsenoside R2 attenuates hepatic fibrosis via STAT3-dependent hepatic stellate cells senescence induction and inflammatory microenvironment suppression.三七皂苷R2通过依赖STAT3诱导肝星状细胞衰老和抑制炎症微环境来减轻肝纤维化。
J Ginseng Res. 2025 Sep;49(5):574-584. doi: 10.1016/j.jgr.2025.05.007. Epub 2025 May 30.
5
Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.丙氨酸分解代谢作为MYC驱动的肝癌的一个可靶向的脆弱点。
bioRxiv. 2025 Aug 12:2025.07.29.667471. doi: 10.1101/2025.07.29.667471.
6
Dynamic crosstalk between HSCs and liver microenvironment: multicellular interactions in the regulation of liver fibrosis.肝星状细胞与肝脏微环境之间的动态串扰：肝脏纤维化调控中的多细胞相互作用
Front Cell Dev Biol. 2025 Jul 21;13:1635763. doi: 10.3389/fcell.2025.1635763. eCollection 2025.
7
FBP1 as a key regulator of focal adhesion kinase-mediated hepatic stellate cell activation: Multi-omics and experimental validation.FBP1作为粘着斑激酶介导的肝星状细胞激活的关键调节因子：多组学及实验验证
World J Gastroenterol. 2025 Jul 28;31(28):107361. doi: 10.3748/wjg.v31.i28.107361.
8
Integrative analysis of thiamethoxam induced hepatocellular carcinoma toxicity mechanisms.噻虫嗪诱导肝细胞癌毒性机制的综合分析
Sci Rep. 2025 Jul 22;15(1):26544. doi: 10.1038/s41598-025-11792-3.
9
NFATc1 facilitates hepatocellular carcinoma progression by regulating the senescence-associated secretory phenotype.NFATc1通过调节衰老相关分泌表型促进肝细胞癌进展。
Sci Rep. 2025 Jul 10;15(1):24824. doi: 10.1038/s41598-025-07585-3.
10
MLN4924 suppresses tumor metabolism and growth of clear cell renal cell carcinoma by stabilizing nuclear FBP1.MLN4924通过稳定细胞核中的FBP1来抑制透明细胞肾细胞癌的肿瘤代谢和生长。
Cell Death Discov. 2025 May 26;11(1):253. doi: 10.1038/s41420-025-02426-8.
Nature. 2019 Oct;574(7777):268-272. doi: 10.1038/s41586-019-1607-3. Epub 2019 Oct 2.
4
Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies.线粒体重编程是淋巴恶性肿瘤对 BCL-2 抑制产生耐药的基础。
Cancer Cell. 2019 Oct 14;36(4):369-384.e13. doi: 10.1016/j.ccell.2019.08.005. Epub 2019 Sep 19.
5
The dynamic nature of senescence in cancer.衰老在癌症中的动态特性。
Nat Cell Biol. 2019 Jan;21(1):94-101. doi: 10.1038/s41556-018-0249-2. Epub 2019 Jan 2.
6
Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?研究 NASH 驱动 HCC 的临床前模型：它们有多大用处？
Cell Metab. 2019 Jan 8;29(1):18-26. doi: 10.1016/j.cmet.2018.10.012. Epub 2018 Nov 15.
7
Senolytics improve physical function and increase lifespan in old age.衰老细胞清除疗法可改善老年的身体机能并延长寿命。
Nat Med. 2018 Aug;24(8):1246-1256. doi: 10.1038/s41591-018-0092-9. Epub 2018 Jul 9.
8
Mechanisms of NAFLD development and therapeutic strategies.非酒精性脂肪性肝病发病机制及治疗策略。
Nat Med. 2018 Jul;24(7):908-922. doi: 10.1038/s41591-018-0104-9. Epub 2018 Jul 2.
9
High Mobility Group Box-1 Drives Fibrosis Progression Signaling via the Receptor for Advanced Glycation End Products in Mice.高迁移率族蛋白 B1 通过糖基化终产物受体驱动小鼠纤维化进程信号转导。
Hepatology. 2018 Dec;68(6):2380-2404. doi: 10.1002/hep.30093. Epub 2018 Nov 13.
10
A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer.一种简单的饮食和化学诱导的 NASH 小鼠模型，其肝脂肪性肝炎、纤维化和肝癌的进展迅速。
J Hepatol. 2018 Aug;69(2):385-395. doi: 10.1016/j.jhep.2018.03.011. Epub 2018 Mar 21.