摘要
AIM： To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma （HCC）. METHODS： Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting. RESULTS： Erlotinib treatment inhibited the mitogen activated protein （MAP）-kinase pathway and signal transducer of activation and transcription （STAT）- mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-XL or jun D accounted for erlotinib＇s potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib＇s inhibitory effects on the receptor-receptor cross talk. CONCLUSION： Our study sheds light on the understanding of the mechanisms of action of EGFR-TK- inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future.
瞄准：在肝细胞癌(HCC ) 检验导致 erlotinib 的生长抑制的内在的机制。方法：在基因表示的导致 Erlotinib 的改变用 cDNA 数组技术被评估；在蛋白质表示或蛋白质激活的变化用西方的弄污由于象 IGF-1-induced EGFR transactivation 一样的 erlotinib 治疗被调查。结果：Erlotinib 治疗禁止了 mitogen 激活和抄写(STAT ) 的激活的蛋白质(地图)-kinase 小径和信号变换器调停了表明哪个导致了调整由 cDNA 数组技术示威了的基因的 apoptosis 和房间周期的一个改变的表达式。象与象 Bcl-2， Bcl-X (L) 或 jun D 一样的 antiapoptotic 因素的一条下面规定联系的 caspases 和 gadds 一样的 proapoptotic 因素的 Overexpression 说明了让 erlotinib 的力量导致 apoptosis。支持 G1/S-transition 的房间周期管理者并且在 cyclin 依赖的激酶禁止者和 gadds 的表示上的 Downregulation 响应 erlotinib 贡献了 G1/G0-arrest 的正式就职。而且，我们显示了由 IGF-1-receptor 的调停 EGFR 的发信号的 transactivation 并且在受体受体十字谈话显示出 erlotinib 的禁止的效果。结论：我们的学习在 HCC 房间和 thus 使 EGFR-TK-inhibition 的行动的机制的理解清楚些可能便于 additively 或 synergistically 行动的联合治疗的设计。而且，我们对 erlotinib 处理作出回应的小径上的数据能在以后预言肿瘤的应答的海角到 EGFR-TKIs 是有用的。
基金
Supported by Deutsche Forschungsgemeinschaft (DFG),Deutsche Krebshilfe and Sonnenfeld-Stiftung Berlin
