抗癌药物Sorafenib下调AIB1的分子机制及其生物学效应

抗癌药物Sorafenib是一种多激酶抑制剂，它是到目前为止唯一的一种可以较为有效地治疗或是缓解肝细胞癌的分子靶向药物，但Sorafenib抗肝癌的具体分子机制仍不清楚。最近我们发现Sorafenib可以显著下调在肝癌发展中起重要促进作用的转录辅激活因子AIB1蛋白的表达；过表达AIB1可以削弱Sorafenib对肝癌细胞存活的抑制作用，提示Sorafenib可能通过下调AIB1蛋白的表达来发挥其抗肝癌生物学效应。在本项目中我们将验证这一可能，并研究其分子机制。我们拟首先研究Sorafenib下调AIB1蛋白表达的分子机制；其次研究过表达AIB1削弱Sorafenib对肝癌细胞存活抑制作用的分子机制；接着利用肝脏特异性AIB1转基因小鼠来研究肝脏中过表达AIB1对Sorafenib抗肝癌效应的影响；最后综合以上研究结果揭示Sorafenib通过下调AIB1发挥其抗肝癌效应这一新的分子机制。

Sorafenib is a multi-tyrosine kinase inhibitor. So far it is widely used in hepatocellular cancer therapy and has been demonstrated to be one of the most effective anti-HCC molecular targeted drugs.However, its molecular mechanism is still unknown. Here,we report that Sorafenib downregulated protein levels of AIB1, which is a transcription coactivator and play important role in the progression of HCC. Overexpression of AIB1 decreased cell mortality induced by Sorafenib, indicating that Sorafenib by downregulating AIB1 protein expression in the cancer cells. To test this possibility, firstly, we will further dissect the molecular mechanisms how Sorafenib downregulates AIB1 protein levels; secondly, we will study the molecular mechanism by which AIB1 overexpression impairs HCC mortality induced by Sorafenib; thirdly, we will determine the effect of Sorafenib on the progression of DEN-induced liver cancer in AIB1 transgenic mice. Based on the results, we will shed light on molecular mechanism of the anti-tumor effect of Sorafenib by downreguating AIB1 protein in HCC cells.