枸杞糖肽重塑癌细胞Atad3a介导的ERK线粒体转位在逆转靶向耐药中的作用机制研究

传承传统医学扶正驱邪理论明晰靶向耐药的机制，对认识肝癌发生演进机理、探索逆转耐药策略具有重要的理论与实践意义。我们前期研究发现线粒体自噬“超激活”诱导肝癌索拉非尼靶向耐药；中药枸杞糖肽（DPPH）具有重塑线粒体稳态，逆转靶向耐药的生物学效应，但机制不清；进一步证据提示DPPH转录调控自噬核心分子Atad3a，Atad3a缺失促进p-ERK1/2线粒体转位激活耐药细胞线粒体自噬。本项目提出“DPPH抑制miR-210靶向上调Atad3a，通过阻遏“非经典”p-ERK1/2线粒体转位抑制线粒体自噬，逆转索拉非尼耐药”的假说，拟采用RNA-Pulldown、luciferase等技术明确DPPH上调Atad3a的机制；揭示Atad3a介导p-ERK1/2线粒体转位、抑制线粒体自噬在逆转索拉非尼靶向耐药中的临床学意义；结果可望深入认识肿瘤靶向耐药的源动力机制，为逆转耐药治疗策略提供新思路和靶点。

It is of great theoretical and practical significance to understand the mechanism of liver cancer development and explore the strategy of reversing drug resistance. In the previous study, we found that sorafenib resistant liver cancer cell has a hyperactivated mitophagy. And the traditional Chinese medicine medlar glycoprotein (DPPH) has the biological effect of remodeling mitochondrial homeostasis and reversing sorafenib targeted drug resistance, but the mechanism is unclear. Further evidence suggests that DPPH can regulate Atad3a expression, and Atad3a deletion promotes mitophagy by upregulating p-ERK1/2 mitochondrial translocation. This project proposes the hypothesis that DPPH can inhibit miR-210 to target and up regulate Atad3a expression, inhibits mitophagy by limiting the "non classical" p-ERK1/2 mitochondrial translocation, and then reverse sorafenib resistance of liver cancer. We proposed to use RNA-pulldown, luciferase reporter gene detection and other technologies to clarify the mechanism of DPPH up regulating Atad3a expression; to reveal the clinical significance of Atad3a mediated p-ERK1/2 mitochondrial translocation and inhibition of mitophagy in reversing sorafenib targeted drug resistance. Results is expected to further understand the source and dynamic mechanism of tumor targeted drug resistance, and provide new ideas and targets to reverse the drug resistance treatment strategy.