GBP2通过Drp1介导乳腺癌线粒体动态变化和细胞转移的机制研究

Metastasis is the main cause of treatment failure and death in patients with breast cancer. Therefore, it is of great significance to study the mechanism of metastasis for the treatment of breast cancer. Recent studies suggest that Drp1 mediated mitochondrial fission to promote breast cancer metastasis. We first found the following results in the preliminary experiments: GBP2 inhibits mitochondrial division and metastasis of breast cancer cells; GBP2 interacts with Drp1; the expression of Drp1 affects the regulation of GBP2 on the mitochondrial division and metastasis of breast cancer cells. Accordingly, we put forward the hypothesis: GBP2 interacts with Drp1 to regulate the dynamic changes of mitochondria and breast cancer cell migration. To test this hypothesis, we will use a series of methods, such as clinical specimen detection, transwell, flow cytometry detection, confocal scanning, Western-blot, pull-down, Co-IP, RT-PCR, RNAi, xenograft tumor in mice, etc to clarify the interaction between GBP2 with Drp1, and then study the molecular mechanism of the interaction on breast cancer metastasis. We will explore the upstream regulatory genes of GBP2. This study investigates the effect of GBP2 on breast cancer metastasis by Drp1, in order to provide a new direction for the prevention and treatment of breast cancer.

转移是导致乳腺癌治疗失败的主要原因，研究乳腺癌的转移机制对治疗有重要意义。既往研究提示Drp1介导的线粒体分裂促进乳腺癌转移，我们在预实验中首次发现：GBP2抑制乳腺癌细胞的线粒体分裂、转移和侵袭；GBP2与Drp1相互作用；Drp1的表达影响GBP2对乳腺癌细胞线粒体分裂和转移的调控。据此我们提出假说：Drp1是GBP2的新靶点，GBP2通过与Drp1的相互作用调控线粒体分裂-融合动态变化从而参与乳腺癌细胞转移的调节。为验证该假设，我们拟运用临床标本检测、在高/低转移乳腺癌细胞中采用Transwell、激光共聚焦、Western-blot、Co-IP、RT-PCR、基因沉默/过表达、肿瘤动物模型验证等手段，阐明GBP2与Drp1如何相互作用并影响乳腺癌转移的分子机制，并探索GBP2的上游调控基因。本研究从GBP2通过Drp1抑制乳腺癌转移的新视点进行多层次研究，为乳腺癌防治提供新方向。

转移是导致乳腺癌治疗失败、患者死亡的主要原因。目前乳腺癌转移的分子机制仍存在争议。本研究通过组织病理学、蛋白组学、分子生物学、动物模型等手段，围绕“Drp1是GBP2的新靶点，GBP2通过与Drp1蛋白的相互作用调控线粒体的分裂-融合动态变化从而参与乳腺癌细胞转移的调节”的新视点开展多层次研究，阐明GBP2与Drp1如何相互作用并影响乳腺癌转移的分子机制。本项目对于深入了解和揭示乳腺癌恶性进展分子机制不仅具有重要的理论意义，且本项目中研究对象GBP2和Drp1都可作为乳腺癌潜在治疗的新靶点，通过基础研究与临床转化性应用紧密结合，有望为乳腺癌治疗提供一些新思路和新靶点。并在项目的支持下，发表SCI论文3篇，获得省级自然科学奖三等奖、医学科学奖二等奖各1项；培养硕士研究生2名、攻读博士1人；申请发明专利2项；参与国内外学术交流；帮助团队成员完成晋升职称晋升2人。