The preventative effect of Akt knockout on liver cancer through modulating NF-κB-regulated inflammation and Bad-related apoptosis signaling pathway
The preventative effect of Akt knockout on liver cancer through modulating NF-κB-regulated inflammation and Bad-related apoptosis signaling pathway
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DOI：
10.3892/ijo.2016.3383
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发表时间：
2016-04-01
影响因子：
5.2
通讯作者：
Lin, Qin
中科院分区：
文献类型：
--
作者：
Hu, Bin;Sun, Ming;Lin, Qin
原发性肝癌是全球第六大常见癌症，是世界第二大癌症死亡原因，在许多国家其发病率呈上升趋势，严重威胁着人类的健康。大量研究集中在肝癌的治疗和预防上。然而，肝癌的潜在分子机制仍不完全清楚，从而延缓了治疗方法的发展。AKT被认为在炎症反应和细胞凋亡的过程中发挥重要作用。因此，本研究以Akt基因敲除小鼠和肝癌细胞系为模型，探讨Akt相关的炎症和凋亡信号通路与核因子-kappaB和Bad在肝癌发生发展中的分子机制。采用Western blotting、定量RT-PCR、免疫组织化学、酶联免疫吸附试验和流式细胞仪等方法分析肝癌发生发展过程中的信号转导途径。结果表明，与正常肝细胞相比，肝癌细胞株Akt的表达明显增强。此外，Akt基因敲除的肝癌细胞Akt表达较低。我们还发现，Akt基因敲除的癌细胞系通过抑制核因子-kappa B的表达和抑制凋亡激活来调控炎症反应和细胞凋亡。我们的结果表明，在Akt基因敲除过程中，下游信号，包括受核因子-kappaB信号通路调节的细胞因子和受Bad影响的caspase-3激活的细胞凋亡被下调。这些发现表明Akt与核因子-kappaB和Bad信号通路有关，可能在肝癌的发生发展中起直接作用。因此，Akt可能是未来临床诊断和治疗的一个重要且有潜力的治疗选择。
Primary liver cancer is globally the sixth most frequent cancer, and the second leading cause of cancer death and its incidence is increasing in many countries, thus, becoming serious threat to human health. Substantial research has focused on the treatment and prevention of liver cancer. However, the underlying molecular mechanism of liver cancer are still not fully understood, and therefore development of treatments are delayed. Akt has been suggested to play an essential role in the progression of inflammation response and apoptosis. Hence, in the present study, Akt knockout mice and cell lines were used as a model to investigate the molecular mechanism of Akt-associated inflammatory and apoptotic signaling pathway with NF-kappa B and Bad in the progression of liver cancer. Western blotting, quantitative RT-PCR (qRT-PCR), immunohistochemistry, ELISA and flow cytometric analysis were used to determine the key signaling pathway in the development of liver cancer. The results indicated that, compared to the normal liver cells, the expression of Akt was significantly higher in liver cancer cell lines. In addition, Akt-knockout liver cancer cells showed lower Akt expression. we also, found that Akt-knockout cancer cell lines modulated inflammation response and apoptosis via inhibiting NF-kappa B expression and suppressing apoptotic activation. Our results indicated that the downstream signals, including cytokines regulated by NF-kappa B signaling pathway and caspase-3-activated apoptosis affected by Bad were downregulated for knockout of Akt. These findings demonstrated that Akt is related to NF-kappa B and Bad signaling pathway possibly playing a direct role in the progression of liver cancer. Thus, Akt might be an important and potential treatment choice for the clinical diagnosis and treatment in the future.