MCUR1介导线粒体钙稳态重塑调控肝癌生长转移的作用机制研究

Cancer cells typically exhibit disease promoting characteristics linked to alterations in mitochondrial function, including increased glycolysis and reactive oxygen species (ROS) production, and resistance to apoptotic stimuli. Although mitochondrial Ca2+ homeostasis has been shown to participate in the control of the intrinsic pathway of apoptosis and to be influenced by oncogenes, very little is known about mitochondrial Ca2+ regulation or its signaling in cancer. In previous study, we have demonstrated that recently identified protein MCUR1, a key regulator of mitochondrial Ca2+ channel protein, is highly expressed on hepatocellular carcinoma (HCC), and palys a critical role in promoting cell survival and metastasis in HCC cells, not only indicating that it maybe a key molecule invovled in tumor progression, but also suggesting that MCUR1-mediated mitochondrial Ca2+ homeostasis remolding may be a signaling checkpoint in tumorigenesis. Therefore, based on our previous understanding on the mitochondria and HCC, we aim to elucidate the biological functions of MCUR1 in HCC progression, thus to comprehensively explain the mechanisms involved in the regulation of mitochondrial Ca2+ homeostasis remolding induced malignant tramsformation of HCC cells. This project will facililate the understanding on molecular pathology of HCC and provide new potential targets for HCC treatment.

线粒体钙稳态对于线粒体功能及细胞生物活性的影响至关重要，线粒体钙稳态重塑是多种疾病发生的主要原因，但这一改变是否在肿瘤恶性进展中发挥关键作用尚无明确报道。我们前期研究获得重要发现：肝癌细胞中调节线粒体钙摄取的关键分子MCUR1表达异常升高，显著促进肝癌细胞增殖与转移能力，而这一变化与线粒体钙稳态重塑介导的活性氧ROS水平上调及其下游AKT信号通路活化密切相关。基于此，我们提出假说：MCUR1上调引发线粒体钙稳态重塑，通过调控ROS生成并影响其下游信号网络，最终促进肝癌细胞恶性转化。本项目拟在以往线粒体与肝癌研究的工作基础上，从新近发现的线粒体蛋白功能研究入手，深入探索线粒体钙稳态改变对肝癌细胞恶性转化的生物学影响，探讨关键信号通路的改变，进而系统阐明线粒体钙稳态重塑参与肝癌细胞恶性进展的分子机制。本项目的完成将为深入理解线粒体功能异常对肿瘤发展的影响提供新思路，为肝癌治疗提供潜在的新靶点。

线粒体钙稳态对于线粒体功能及细胞生物活性的影响至关重要，线粒体钙稳态重塑是多种疾病发生的主要原因，但这一改变是否在肿瘤恶性进展中发挥关键作用尚无明确报道。我们前期研究获得重要发现：肝癌细胞中调节线粒体钙摄取的关键分子MCUR1表达异常升高，显著促进肝癌细胞增殖与转移能力，而这一变化与线粒体钙稳态重塑介导的活性氧ROS水平上调及其下游AKT信号通路活化密切相关。基于此，我们提出假说：MCUR1上调引发线粒体钙稳态重塑，通过调控ROS生成并影响其下游信号网络，最终促进肝癌细胞恶性转化。本项目拟在以往线粒体与肝癌研究的工作基础上，从新近发现的线粒体蛋白功能研究入手，深入探索线粒体钙稳态改变对肝癌细胞恶性转化的生物学影响，探讨关键信号通路的改变，进而系统阐明线粒体钙稳态重塑参与肝癌细胞恶性进展的分子机制。本项目的完成将为深入理解线粒体功能异常对肿瘤发展的影响提供新思路，为肝癌治疗提供潜在的新靶点。