CHCHD2 及其介导的线粒体功能在乳腺癌转移过程中的作用机制研究

Escalating evidences suggest that mitochondrion is indispensible for metastatic breast cancer. However, the linker between mitochondria and metastasis signaling is missing. Recently, we found that CHCHD2, a mitochondrial protein involved in the regulation of oxidative phosphorylation, is highly expressed in breast cancer patient samples. Moreover, high level of CHCHD2 is statistically correlated with worse prognosis in breast cancer patients. Biochemistry studies revealed that CHCHD2 is able to sense high ROS, which is one of the hallmarks in tumor microenvironment. By neutralizing ROS through its CX9C motif, CHCHD2 changes its conformation and translocates from mitochondria to cytoplasm and nuclear where it acquires the allosteric potential to crosstalk and trigger non-mitochondrial events such as metastasis. Meanwhile, loss of CHCHD2 from mitochondria could cause mitochondrial dysfunction and caner beneficial metabolic reprogramming. In this current proposal, we will study the relationship between CHCHD2 and metastatic mechanisms with in vitro and in vivo system. We will also recruit proteomics method as well as differential display microarray to further uncover the downstream signals which are related to the regulation of metastasis by CHCHD2. This study will provide insight in understanding how mitochondria machinery mediates cancer metastasis. The fulfillment of this proposal will also shed light on the discovery of novel therapeutic targets for metastatic breast cancer.

线粒体功能参与介导乳腺癌转移是近来的研究热点，然而线粒体与转移机制的联接点是一个缺失环节。我们的前期研究显示线粒体蛋白CHCHD2在乳腺癌中高表达并与不良预后相关。对于CHCHD2的分析发现该蛋白通过其富含半胱氨酸的CX9C结构域感应细胞外的氧应激，由还原态的单体转化为氧化态的寡聚体，导致蛋白构象变化并由线粒体释放进入细胞质和细胞核，这一系列的变化为线粒体蛋白CHCHD2调控非线粒体信号如转移机制提供了空间基础。本课题将致力于从分子、细胞、动物模型以及临床样本的不同层次研究CHCHD2与乳腺癌转移的关系，并将结合蛋白质组学以及基因表达差异显示芯片发现CHCHD2调控肿瘤转移的分子机制。本课题的成功实施将为理解线粒体如何参与并介导癌症尤其是乳腺癌转移提供新的思路，同时可以为晚期转移乳腺癌提供新的肿瘤标志物甚至是药物靶标。

线粒体是细胞代谢、氧化还原和细胞命运决定的焦点。线粒体功能在肿瘤进展中的作用是近年来肿瘤代谢领域一个存在争议的领域。根据肿瘤组织器官来源不同，或者肿瘤进展的不同阶段，线粒体可能发挥完全相反的作用。因此，理解肿瘤细胞中线粒体感应并传导氧化应激信号，从而调节代谢，决定细胞命运的具体机制具有重要意义。项目前期发现线粒体内一类功能未知的巯基富含蛋白CHCHD2介导细胞凋亡拮抗并在肿瘤细胞显著高表达。本项目中，我们从分子、细胞到整体角度鉴定了CHCHD2蛋白的细胞生物学功能，调控机制及其对于肿瘤细胞增殖和转移的影响。研究发现，CHCHD2在线粒体呼吸中发挥重要作用，同时抑制线粒体自由基水平；细胞内的CHCHD2半衰期约3.5小时，通过氨基端序列介导其溶酶体途径降解；CHCHD2促进乳腺癌细胞增殖和迁移，在乳腺癌组织中CHCHD2高表达，且与乳腺癌不良预后相关。此外，CHCHD2互作蛋白p32调节内质网蛋白折叠从而调控脂肪酸合成及机体脂肪储备。本课题的开展为进一步理解线粒体如何参与肿瘤进展及耐药提供了新的思路，同时可以为乳腺癌提供新的肿瘤标志物甚至是药物靶标。