Institute of Biomedicine and Molecular Immunology Alberto Monroy, National Research Council (CNR), Palermo, Italy.
Cell Cycle. 2012 Aug 1;11(15):2843-55. doi: 10.4161/cc.21193.
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 anti-tumor 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.
索拉非尼是一种多激酶抑制剂，最近获得了 FDA 批准用于治疗晚期肝细胞癌（HCC）。然而，随着索拉非尼的临床应用不断发展，人们越来越关注其抗肿瘤活性的潜在机制。考虑到这种特定的抑制剂可能根据生物背景靶向意想不到的分子，因此精确了解其作用机制对于最大限度地提高其治疗效果，同时最小化不良反应至关重要。本研究使用两种具有不同生物学和遗传特征的人 HCC 细胞系（HepG2 和 Huh7）来研究导致索拉非尼诱导 HCC 细胞生长抑制的细胞内事件。索拉非尼以剂量和时间依赖性方式抑制两种细胞系的细胞生长，并显著改变 HepG2 和 Huh7 细胞中 826 和 2011 个转录本的表达水平。功能上涉及血管生成、凋亡、转录调节、信号转导、蛋白质生物合成和修饰的基因主要上调，而涉及细胞周期控制、DNA 复制、重组和修复、细胞黏附、代谢和运输的基因主要下调。然而，每种索拉非尼处理的 HCC 细胞系在参与肝癌发生的关键因素的表达和活性方面表现出特异性。这些基因中的一些的表达变化通过半定量和定量 RT-PCR 以及 Western blot 得到了证实。我们的转录组学分析中出现了许多新的基因，这些基因以前没有报道过受索拉非尼的影响。进一步的功能分析可能确定这些基因是否可以作为更有效的抗 HCC 策略的潜在分子靶标。
