Smad3通过下调Bcl-2使肝细胞对凋亡敏感，从而降低肝癌易感性。
Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2.
作者信息
Yang Yu-An, Zhang Gen-Mu, Feigenbaum Lionel, Zhang Ying E
机构信息
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
出版信息
Cancer Cell. 2006 Jun;9(6):445-57. doi: 10.1016/j.ccr.2006.04.025.
Abstract
In the liver, derangement of TGF-beta signaling is associated with an increased incidence of hepatocellular carcinoma (HCC), but the mechanism is not clear. We report here that forced expression of a major TGF-beta signaling transducer, Smad3, reduces susceptibility to HCC in a chemically induced murine model. This protection is conferred by Smad3's ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter. We also show that the proapoptotic activity of Smad3 requires both input from TGF-beta signaling and activation of p38 MAPK, which occurs selectively in the liver tumor cells. Thus, Smad3 enables the tumor suppression function of TGF-beta by serving as a physiological mediator of TGF-beta-induced apoptosis.
摘要
在肝脏中，转化生长因子β（TGF-β）信号传导紊乱与肝细胞癌（HCC）发病率增加相关，但机制尚不清楚。我们在此报告，在化学诱导的小鼠模型中，一种主要的TGF-β信号转导分子Smad3的强制表达降低了对HCC的易感性。这种保护作用是由Smad3通过Bcl-2启动子中富含GC的元件在体内抑制Bcl-2转录来促进细胞凋亡的能力赋予的。我们还表明，Smad3的促凋亡活性既需要TGF-β信号传导的输入，也需要p38丝裂原活化蛋白激酶（p38 MAPK）的激活，而p38 MAPK的激活选择性地发生在肝肿瘤细胞中。因此，Smad3通过作为TGF-β诱导的细胞凋亡的生理介质，实现了TGF-β的肿瘤抑制功能。
相似文献
1
Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2.Smad3通过下调Bcl-2使肝细胞对凋亡敏感，从而降低肝癌易感性。
Cancer Cell. 2006 Jun;9(6):445-57. doi: 10.1016/j.ccr.2006.04.025.
2
Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1.肝细胞中转化生长因子-β信号的转导促进了 TAK1 肝细胞特异性缺失小鼠的肝纤维化和肝癌发生。
Gastroenterology. 2013 May;144(5):1042-1054.e4. doi: 10.1053/j.gastro.2013.01.056. Epub 2013 Feb 4.
3
Gamma-linolenic acid inhibits hepatic PAI-1 expression by inhibiting p38 MAPK-dependent activator protein and mitochondria-mediated apoptosis pathway.γ-亚麻酸通过抑制p38丝裂原活化蛋白激酶依赖性激活蛋白和线粒体介导的凋亡途径来抑制肝脏纤溶酶原激活物抑制剂-1的表达。
Apoptosis. 2015 Mar;20(3):336-47. doi: 10.1007/s10495-014-1077-x.
4
TGF beta-mediated BIM expression and apoptosis are regulated through SMAD3-dependent expression of the MAPK phosphatase MKP2.转化生长因子β介导的BIM表达和细胞凋亡是通过丝裂原活化蛋白激酶磷酸酶MKP2的SMAD3依赖性表达来调节的。
EMBO Rep. 2008 Oct;9(10):990-7. doi: 10.1038/embor.2008.158. Epub 2008 Aug 15.
5
Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis.一种显性负性突变型转化生长因子-β II型受体的肝细胞表达加速化学诱导的肝癌发生。
Oncogene. 2001 Aug 16;20(36):5015-24. doi: 10.1038/sj.onc.1204544.
6
Transforming Growth Factor-β Promotes Liver Tumorigenesis in Mice via Up-regulation of Snail.转化生长因子-β 通过上调 Snail 促进小鼠肝癌发生。
Gastroenterology. 2017 Nov;153(5):1378-1391.e6. doi: 10.1053/j.gastro.2017.07.014. Epub 2017 Jul 20.
7
Caveolin-1 abrogates TGF-β mediated hepatocyte apoptosis.窖蛋白-1 废除 TGF-β 介导的肝细胞凋亡。
Cell Death Dis. 2013 Jan 17;4(1):e466. doi: 10.1038/cddis.2012.204.
8
Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro.Smad7 在小鼠和体外肝癌发生中的抑制作用。
J Pathol. 2013 Aug;230(4):441-52. doi: 10.1002/path.4206.
9
Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss.转化生长因子-β信号促进 p53 缺失诱导的肝癌发生。
Hepatology. 2012 Jan;55(1):121-31. doi: 10.1002/hep.24653. Epub 2011 Dec 6.
10
Potentiation of Smad transactivation by Jun proteins during a combined treatment with epidermal growth factor and transforming growth factor-beta in rat hepatocytes. role of phosphatidylinositol 3-kinase-induced AP-1 activation.在大鼠肝细胞中，表皮生长因子和转化生长因子-β联合处理期间Jun蛋白对Smad反式激活的增强作用。磷脂酰肌醇3激酶诱导的AP-1激活的作用。
J Biol Chem. 2001 Mar 30;276(13):10524-31. doi: 10.1074/jbc.M005919200. Epub 2000 Dec 27.
引用本文的文献
1
NSUN5 Facilitates Hepatocellular Carcinoma Progression by Increasing SMAD3 Expression.NSUN5通过增加SMAD3表达促进肝细胞癌进展。
Adv Sci (Weinh). 2025 Jan;12(2):e2404083. doi: 10.1002/advs.202404083. Epub 2024 Nov 12.
2
Hepatitis B virus X protein and TGF-β: partners in the carcinogenic journey of hepatocellular carcinoma.乙型肝炎病毒X蛋白与转化生长因子-β：肝细胞癌致癌进程中的伙伴
Front Oncol. 2024 Jun 19;14:1407434. doi: 10.3389/fonc.2024.1407434. eCollection 2024.
3
The Role of TGF-β/SMAD Signaling in Hepatocellular Carcinoma: from Mechanism to Therapy and Prognosis.TGF-β/SMAD 信号通路在肝细胞癌中的作用：从机制到治疗和预后。
Int J Biol Sci. 2024 Feb 4;20(4):1436-1451. doi: 10.7150/ijbs.89568. eCollection 2024.
4
Development and evaluation of a risk score model based on a WNT score gene-associated signature for predicting the clinical outcome and the tumour microenvironment of hepatocellular carcinoma.基于 WNT 评分基因相关特征的风险评分模型的开发和评估，用于预测肝细胞癌的临床结局和肿瘤微环境。
Int J Immunopathol Pharmacol. 2023 Jan-Dec;37:3946320231218179. doi: 10.1177/03946320231218179.
5
Modulation of the p38 MAPK Pathway by Anisomycin Promotes Ferroptosis of Hepatocellular Carcinoma through Phosphorylation of H3S10.安丝菌素通过调节 p38 MAPK 通路促进磷酸化 H3S10 诱导肝癌细胞发生铁死亡。
Oxid Med Cell Longev. 2022 Nov 24;2022:6986445. doi: 10.1155/2022/6986445. eCollection 2022.
6
Berberine Suppressed the Progression of Human Glioma Cells by Inhibiting the TGF-β1/SMAD2/3 Signaling Pathway.小檗碱通过抑制 TGF-β1/SMAD2/3 信号通路抑制人神经胶质瘤细胞的进展。
Integr Cancer Ther. 2022 Jan-Dec;21:15347354221130303. doi: 10.1177/15347354221130303.
7
Mutational signatures representative transcriptomic perturbations in hepatocellular carcinoma.肝细胞癌中代表转录组扰动的突变特征。
Front Genet. 2022 Aug 23;13:970907. doi: 10.3389/fgene.2022.970907. eCollection 2022.
8
Research Progress on the Microenvironment and Immunotherapy of Advanced Non-Small Cell Lung Cancer With Liver Metastases.晚期非小细胞肺癌肝转移的微环境与免疫治疗研究进展
Front Oncol. 2022 Jul 28;12:893716. doi: 10.3389/fonc.2022.893716. eCollection 2022.
9
Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options.肝细胞癌的肿瘤微环境：新治疗方案面临的挑战与机遇
Int J Mol Sci. 2022 Mar 29;23(7):3778. doi: 10.3390/ijms23073778.
10
The Molecular Interaction of Collagen with Cell Receptors for Biological Function.胶原蛋白与细胞受体的分子相互作用及其生物学功能
Polymers (Basel). 2022 Feb 23;14(5):876. doi: 10.3390/polym14050876.
本文引用的文献
1
An inhibitor of Bcl-2 family proteins induces regression of solid tumours.一种Bcl-2家族蛋白抑制剂可诱导实体瘤消退。
Nature. 2005 Jun 2;435(7042):677-81. doi: 10.1038/nature03579. Epub 2005 May 15.
2
Global cancer statistics, 2002.2002年全球癌症统计数据。
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108. doi: 10.3322/canjclin.55.2.74.
3
Inactivation of TGF-beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy.肝细胞中转化生长因子-β信号的失活导致部分肝切除术后增殖反应增强。
Oncogene. 2005 Apr 21;24(18):3028-41. doi: 10.1038/sj.onc.1208475.
4
Dual role for TGF-beta1 in apoptosis.转化生长因子β1（TGF-β1）在细胞凋亡中的双重作用。
Cytokine Growth Factor Rev. 2005 Feb;16(1):15-34. doi: 10.1016/j.cytogfr.2004.11.002. Epub 2005 Jan 25.
5
Activation and signaling of the p38 MAP kinase pathway.p38丝裂原活化蛋白激酶信号通路的激活与信号传导。
Cell Res. 2005 Jan;15(1):11-8. doi: 10.1038/sj.cr.7290257.
6
TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions.转化生长因子-β（TGF-β）和肝细胞生长因子（HGF）通过接头区域依赖JNK的Smad2/3磷酸化来传递信号。
Oncogene. 2004 Sep 23;23(44):7416-29. doi: 10.1038/sj.onc.1207981.
7
Loss of Smad3 in acute T-cell lymphoblastic leukemia.急性T淋巴细胞白血病中Smad3的缺失
N Engl J Med. 2004 Aug 5;351(6):552-9. doi: 10.1056/NEJMoa031197.
8
Cyclin-dependent kinases regulate the antiproliferative function of Smads.细胞周期蛋白依赖性激酶调节Smads的抗增殖功能。
Nature. 2004 Jul 8;430(6996):226-31. doi: 10.1038/nature02650.
9
Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis.Akt直接与Smad3相互作用，以调节对转化生长因子-β（TGF-β）诱导的细胞凋亡的敏感性。
Nat Cell Biol. 2004 Apr;6(4):366-72. doi: 10.1038/ncb1117.
10
PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3.蛋白激酶B/Akt通过与Smad3直接相互作用来调节转化生长因子-β信号传导。
Nat Cell Biol. 2004 Apr;6(4):358-65. doi: 10.1038/ncb1113. Epub 2004 Mar 28.
Zotero 插件