金属硫蛋白1G通过p53途径调节肝癌细胞增殖与凋亡

Recently, the abnormal expression and function of metallothionein (MTs) attracted more and more researchers’ attention. MT1G has already been proved as a biomarker for HCC, but its biological function and regulation mechanisms for the deterioration of liver cancer have remained unclear. In our preliminary work, MT1G negatively correlated with the size of HCC, inhibited HCC cells proliferation and apoptosis. Meanwhile, the conformation stability and transcriptional activity of p53 were enhanced due to the overexpression of MT1G. Additionally, the expression of p53 upstream and downstream factors were also regulated, including MDM2, p21, Bax and Cyclin D1. Thus, we propose the possible mechanism: MT1G inhibits the proliferation and promotes the apoptosis of HCC through modulating the p53 signaling pathway. This project intends to confirm our hypothesis at the level of cells and tissues through follow-up experiments. HCC as the research object, focusing on the regulation of MT1G to p53 are our feature and creative. This subject is expected to further understand the regulation mechanism of MT1G and provide a new theoretical basis for MT1G and p53 as a target of anti-HCC therapy.

在肿瘤恶化过程中，金属硫蛋白（Metallothionein，MTs）的表达和功能异常受到肿瘤研究者的高度关注。MT1G是一个已被验证的肝癌标志物，但关于该亚型在肝癌恶化过程中发挥的生物学功能及调节机制仍不清楚。我们的前期工作发现，MT1G与肿瘤的恶化呈显著负相关；过表达MT1G可以抑制肝癌细胞的增殖、促进其凋亡；并且提高p53的表达量和转录活性；以及改变p53上、下游信号分子MDM2、p21、Bax、Cyclin D1的表达。因此我们提出MT1G可能通过增强p53分子的稳定性和转录活性进而激活p53信号对肝癌细胞增殖和凋亡调节。本项目拟通过后续实验，在细胞与动物水平，证实我们的猜测。以肝癌为研究对象，重点研究MT1G对p53的调节是本课题的特色与创新。课题的完成既可加深对MT1G的理解，又为以MT1G为靶点的抗肝癌治疗奠定理论基础。

在肿瘤恶化过程中，金属硫蛋白（Metallothionein，MTs）的表达和功能异常受到肿瘤研究者的高度关注。MT1G是一个已被验证的肝癌标志物，但关于该亚型在肝癌恶化过程中发挥的生物学功能及调节机制仍不清楚。本课题的研究中，我们利用RT-qPCR检测临床组织中MT1G的表达量；利用分子生物学相关技术过表达或敲低肝癌细胞中MT1G的表达量，进而评估MT1G对于细胞增殖的影响。另外co-IP等方法明确MT1G与靶分子的互做等机制研究。结果我们发现，MT1G在肝癌中显著下调表达，与肝癌病人的总生存期显著相关；过表达MT1G可以抑制肝癌细胞的增殖、促进其凋亡；可以通过与p53相互作用增加其转录活性，并且通过抑制其泛素化降解因子MDM2的表达量增加p53的蛋白水平；进而改变p53信号通路下游信号分子p21、Bax的表达，最终实现抑制肝癌细胞增殖的目的。本课题的完成发现并证明了MT1G在肝癌中的生物学作用，并首次发现MT1G与p53之间存在互做，加深了对肝癌细胞快速增殖的理解，为以MT1G为靶点的抗肝癌治疗奠定理论基础。