Molecular mechanisms of sorafenib action in liver cancer cells
Molecular mechanisms of sorafenib action in liver cancer cells
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DOI：
10.4161/cc.21193
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发表时间：
2012-08-01
期刊：
影响因子：
4.3
通讯作者：
Montalto, Giuseppe
中科院分区：
文献类型：
--
作者：
Cervello, Melchiorre;Bachvarov, Dimcho;Montalto, Giuseppe
Sorafenib是一种多激酶抑制剂，最近获得FDA批准用于治疗晚期肝细胞癌（HCC）。然而，随着索拉非尼临床应用的发展，人们对其抗肿瘤活性机制的定义越来越感兴趣。考虑到这种特异性抑制剂可以根据生物学背景靶向意想不到的分子，精确了解其作用机制对于最大限度地提高其治疗效果，同时最大限度地减少不良反应至关重要。本研究使用两种携带不同生物学和遗传特性的人肝癌细胞系HepG2和Huh7，研究导致索拉非尼诱导的肝癌细胞生长抑制的细胞内事件。索拉非尼在两种细胞系中均以剂量和时间依赖的方式抑制细胞生长，并分别显著改变HepG2和Huh7细胞中826和2011转录本的表达水平。参与血管生成、凋亡、转录调控、信号转导、蛋白质生物合成和修饰等功能的基因在处理后以上调为主，而参与细胞周期控制、DNA复制重组和修复、细胞粘附、代谢和运输等功能的基因在处理后以下调为主。然而，每一种索拉非尼治疗的HCC细胞系在参与肝癌发生的关键因子的表达和活性方面都表现出特异性。通过半定量和定量RT-PCR以及western blotting证实了其中一些基因的表达改变。转录组学分析中出现了许多新的基因，以前没有报道过索拉非尼对这些基因的影响。进一步的功能分析可能会确定这些基因是否可以作为更有效的抗hcc策略的潜在分子靶点。
Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced hepatocellular carcinoma (HCC). However, as the clinical application of sorafenib evolves, there is increasing interest in defining the mechanisms underlying its antitumor activity. Considering that this specific inhibitor could target unexpected molecules depending on the biologic context, a precise understanding of its mechanism of action could be critical to maximize its treatment efficacy, while minimizing adverse effects. Two human HCC cell lines (HepG2 and Huh7), carrying different biological and genetic characteristics, were used in this study to examine the intracellular events leading to sorafenib-induced HCC cell-growth inhibition. Sorafenib inhibited cell growth in both cell lines in a dose- and time-dependent manner and significantly altered expression levels of 826 and 2011 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in angiogenesis, apoptosis, transcription regulation, signal transduction, protein biosynthesis and modification were predominantly upregulated, while genes implicated in cell cycle control, DNA replication recombination and repair, cell adhesion, metabolism and transport were mainly downregulated upon treatment. However, each sorafenib-treated HCC cell line displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semiquantitative and quantitative RT-PCR and by western blotting. Many novel genes emerged from our transcriptomics analysis that had not previously been reported to be effected by sorafenib. Further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies.