Autocrine production of TGF-β confers resistance to apoptosis after an epithelial-mesenchymal transition process in hepatocytes:: Role of EGF receptor ligands
Autocrine production of TGF-β confers resistance to apoptosis after an epithelial-mesenchymal transition process in hepatocytes:: Role of EGF receptor ligands
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DOI：
10.1016/j.yexcr.2006.05.017
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发表时间：
2006-09-10
影响因子：
3.7
通讯作者：
Fabregat, Isabel
中科院分区：
文献类型：
--
作者：
del Castillo, Gaelle;Murillo, Miguel M.;Fabregat, Isabel
转化生长因子- β诱导胎鼠肝细胞凋亡。然而，这些细胞的一个亚群存活下来，伴随着表型的变化，让人想起上皮-间质转化（EMT）。我们之前提出EMT可能赋予细胞抗凋亡能力（Valdes et al., Mol. Cancer Res., 1: 68- 78,2002）。然而，这种耐药性的分子机制尚未被探索。在这项工作中，我们分离并传代了遭受EMT过程并对细胞凋亡具有抗性的肝细胞群（tgf - β处理的胎儿肝细胞：T β T- fh）。我们通过条件培养基的增殖和生存能力分析，证明它们分泌有丝分裂因子和生存因子。抑制表皮生长因子受体（EGFR）可使T β T- fh在血清停药后致敏死亡。T β T- fh表达高水平的转化生长因子- α (tgf - α)和肝素结合的egf样生长因子（HB-EGF），并显示EGFR途径的组成性激活。阻断抗tgf - α抗体恢复细胞死亡的能力。tgf - β由T β - fh表达，介导TGF-a和HB-EGF在这些细胞中的表达上调。综上所述，研究结果表明，在肝细胞EMT过程中，tgf - β的自分泌环通过增加EGFR配体的表达来抵抗细胞凋亡。(c) 2006爱思唯尔公司版权所有。
Transforming growth factor-beta (TGF-beta) induces apoptosis in fetal rat hepatocytes. However, a subpopulation of these cells survives, concomitant with changes in phenotype, reminiscent of an epithelial-mesenchymal transition (EMT). We have previously suggested that EMT might confer cell resistance to apoptosis (Valdes et al., Mol. Cancer Res., 1: 68-78, 2002). However, the molecular mechanisms responsible for this resistance are not explored yet. In this work, we have isolated and subcultured the population of hepatocytes that suffered the EMT process and are resistant to apoptosis (TGF-beta-treated fetal hepatocytes: T beta T-FH). We prove that they secrete mitogenic and survival factors, as analyzed by the proliferative and survival capacity of conditioned medium. Inhibition of the epidermal growth factor receptor (EGFR) sensitizes T beta T-FH to die after serum withdrawal. T beta T-FH expresses high levels of transforming growth factor-alpha (TGF-alpha) and heparin-binding EGF-like growth factor (HB-EGF) and shows constitutive activation of the EGFR pathway. A blocking anti-TGF-alpha antibody restores the capacity of cells to die. TGF-beta, which is expressed by T beta T-FH, mediates up-regulation of TGF-a and HB-EGF expression in those cells. In summary, results suggest that an autocrine loop of TGF-beta confers resistance to apoptosis after an EMT process in hepatocytes, through the increase in the expression of EGFR ligands.(c) 2006 Elsevier Inc. All rights reserved.