PKCη-Rhot2信号轴调控线粒体稳态及肾透明细胞癌骨转移的机制和功能研究

骨是肾癌最常见的转移部位之一。由于缺乏有效的治疗靶点，骨相关事件已成为晚期肾癌患者的首要死亡原因。面对这一治疗困境，课题组前期通过生物信息学和临床数据分析发现，调控线粒体稳态的关键蛋白Rhot2与肾透明细胞癌的骨转移密切相关，抑制Rhot2可显著降低肾癌细胞的迁移、骨转移和破骨分化。线粒体是细胞内能量产生和代谢的中枢。线粒体稳态异常与肿瘤发生密切相关，靶向线粒体的治疗策略有望成为肿瘤研究和药物开发的新方向。鉴于此，课题组以Rhot2蛋白为切入点，通过全基因组CRISPR/Cas9激酶筛选发现PKCη可对Rhot2 S156进行磷酸化修饰，从而提高蛋白稳定性。课题组拟进一步利用分子、细胞、动物实验结合临床标本，阐释PKCη-Rhot2信号轴影响线粒体稳态及肾透明细胞癌骨转移的分子机制和功能调控，并评估PKCη抑制剂对肾透明细胞癌骨转移的疗效，为靶向线粒体的肾透明细胞癌骨转移治疗提供新思路。

Bone is one of the most common metastatic sites of renal carcinoma. Due to the lack of effective targets, skeletal-related events have become the leading cause of renal carcinoma mortality. Facing this treatment dilemma, we previously performed an unbiased bioinformatics and clinical analysis that demonstrated that mitochondrial-associated GTPase protein Rhot2 was significantly correlated with the bone metastasis of clear cell renal cell carcinoma (ccRCC). Additionally, inhibition of Rhot2 significantly reduced the renal cell migration, cancer-cell induced osteoclastic differentiation as well as bone metastasis. Mitochondrion is the hub of intracellular energy production and metabolism. The dysregulation of mitochondrial homeostasis contributes to the progression of many cancers. Thus, targeting mitochondrion is one of the most promising strategies for drug development and cancer treatment. Therefore, by utilizing the CRISPR/Cas9-based genome-wide kinase library screening, we found that PKCη could phosphorylate Rhot2 at S156 site, increasing the stability of Rhot2. Based on the previous discoveries, we will use a range of molecular, cell biology, animal and clinical approaches to further investigate the role of PKCη-Rhot2 axis in regulating mitochondrial homeostasis and ccRCC bone metastasis, evaluate the potential therapeutic effect of PKCη inhibitor on the treatment of ccRCC bone metastasis, and provide a novel direction for the future study.