Dissecting the effect of targeting the epidermal growth factor receptor on TGF-β-induced-apoptosis in human hepatocellular carcinoma cells
Dissecting the effect of targeting the epidermal growth factor receptor on TGF-β-induced-apoptosis in human hepatocellular carcinoma cells
复制标题
DOI：
10.1016/j.jhep.2010.10.041
复制
发表时间：
2011-08-01
影响因子：
25.7
通讯作者：
Fabregat, Isabel
中科院分区：
文献类型：
--
作者：
Caja, Laia;Sancho, Patricia;Fabregat, Isabel
背景与目的：转化生长因子β诱导肝细胞凋亡，该过程受表皮生长因子受体(EGFR)途径的抑制。本研究的目的是去除肝癌细胞中的表皮生长因子受体，以了解其在抑制转化生长因子-β诱导的细胞死亡中的作用。方法：分析不同肝癌细胞系对转化生长因子-β诱导的细胞凋亡的反应，并评价其取消EGFR表达的效果。结果：转化生长因子-β可诱导某些肝癌细胞(如Hep3B、PLC/PRF/5、Huh7或SNU449)的凋亡，但也可介导生存信号，与EGFR配体的上调一致。通过用特定的siRNA靶向敲除或通过药物抑制来抑制EGFR，显著增强了细胞的凋亡反应。在EGFR靶向敲除细胞中进行转化生长因子-β治疗与较高水平的NADPH氧化酶NOX4以及bcl2和IAP家族表达谱的变化相关。然而，其他肝癌细胞，如表现出RAS/ERKs通路过度激活的HepG2，具有内皮表型的SK-Hep1，或改变了转化生长因子-β-Smad信号的SNU398，表现出不能通过阻断EGFR而恢复的凋亡抵抗。结论：抑制EGFR在肝癌中可能增强了转化生长因子-β诱导的促凋亡信号。然而，这种效应可能只涉及那些上皮表型的肿瘤，这些肿瘤没有承受转化生长因子-β信号的改变，也没有表现出EGFR下游生存通路的过度激活。(C)2010年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes, a process that is inhibited by the epidermal growth factor receptor (EGFR) pathway. The aim of this work was to ablate EGFR in hepatocellular carcinoma (HCC) cells to understand its role in impairing TGF-beta-induced cell death.Methods: Response to TGF-beta in terms of apoptosis was analyzed in different HCC cell lines and the effect of canceling EGFR expression was evaluated.Results: TGF-beta induces apoptosis in some HCC cells (such as Hep3B, PLC/PRF/5, Huh7, or SNU449), but it also mediates survival signals, coincident with the up-regulation of EGFR ligands. Inhibition of the EGFR, either by targeted knock-down with specific siRNA or by pharmacological inhibition, significantly enhances apoptotic response. TGF-beta treatment in EGFR targeted knock-down cells correlates with higher levels of the NADPH oxidase NOX4 and changes in the expression profile of BCL-2 and IAP families. However, other HCC cells, such as HepG2, which show over activation of the Ras/ERKs pathway, SK-Hep1, with an endothelial phenotype, or SNU398, where the TGF-beta-Smad signaling is altered, show apoptosis resistance that is not restored through EGFR blockade.Conclusions.: The inhibition of EGFR in HCC may enhance TGF-beta-induced pro-apoptotic signaling. However, this effect may only concern those tumors with an epithelial phenotype which do not bear alterations in TGF-beta signaling nor exhibit an over-activation of the survival pathways downstream of the EGFR. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.