线粒体转录因子TFAM调控ROS信号抑制肝癌生长的作用机制

It has been demonstrated that mitochondrial respiratory chain played a pivotal role in maintaining mitochondrial reactive oxygen species (ROS) homeostasis. Elevated ROS levels is closely associated with tumor progression. Mitochondrial transcription factor A (TFAM) was cloned as an important transcription factor for mitochondrial DNA, which encoded 13 key subunits of the respiratory chain complexes. However, the function of TFAM in tumor remains largely unknown. Our preliminary researches revealed that expression of TFAM decreased significantly in hepatocellular carcinoma (HCC) tissues. Expression level of TFAM was negatively correlated with HCC TNM stage and prognosis of patient with HCC. Moreover, we demonstrated that overexpression of TFAM inhibited proliferation and promoted apoptosis of HCC cell. Meanwhile, mitochondrial ROS level was downregulated in HCC cells with TFAM overexpression. Taken together, these results suggested that TFAM might inhibits growth of hepatocellular carcinoma via regulation of mitochondrial ROS signaling. However, the underlying mechanism remains unclear. In the present project, we sought to analyze the function of TFAM in growth of HCC using the tumor biobank we have constructed, as well as the TFAM knockout mouse model we have obtained. Meanwhile, ROS signaling mediated function of TFAM in progression of HCC will be uncovered in nude mouse model using small animal in vivo imaging system. Finally, we will also further investigate upstream regulatory mechanism, which results in downregulation of TFAM in HCC. The present study will helpful to explore the function and of TFAM in progression of HCC and underlying mechanism, as well as provide new potential therapeutic targets for HCC therapy.

线粒体呼吸链是维持细胞活性氧（ROS）动态平衡的关键环节，ROS平衡紊乱与肿瘤发生发展密切相关。线粒体转录因子（TFAM）通过转录调控各呼吸链复合体关键亚基的合成，参与线粒体功能的维持，但关于TFAM在肿瘤中的作用尚不清楚。我们前期发现：TFAM在肝癌组织中表达显著下调，且与患者TNM分期及预后相关；过表达TFAM抑制肝癌细胞增殖，促进凋亡，并下调线粒体ROS水平。这些结果强烈提示TFAM可能通过调控线粒体ROS抑制肝癌的生长，具体机制仍待进一步阐明。本项目拟利用课题组已建立的肝癌病理标本库、TFAM基因敲除小鼠、肝癌细胞系，从临床标本、动物、细胞、分子等多层面，明确TFAM在肝癌生长中的作用；阐明TFAM通过调控ROS信号对肝癌细胞增殖、凋亡的影响及具体分子机制；并探讨TFAM在肝癌中低表达的原因。研究结果将首次阐明TFAM在肝癌中的生物学功能，并有望为肝癌治疗提供潜在靶点和新思路。