GDF15影响卵巢癌化疗耐药的分子机制及靶向抑制研究

Ovarian cancer (OC) is inclined to relapse after surgery, chemotherapy resistance is an important factor of affecting clinical outcomes in patients with OC. Growth differentiation factor 15 (GDF15) is a secreted cytokine of TGF-β superfamily. Our previous study confirmed that the expression of GDF15 significantly increased in OC tumor cells and secreted into the extracellular as a regulatory cytokine, and elevated serum GDF15 levels was significantly associated with Progression-Free-Survival (PFS) and chemotherapy resistance in patients. Transcriptional profiling and proteomics study found that the sensitivity of ovarian cancer cells to chemotherapeutic drugs which affected by GDF15 may predominantly related to the Akt signaling pathway. This study intends to use the Akt kinase regulated by GDF15 as a breaking point, studying the intermediate process of Akt activation by GDF15 and the change of downstream chemotherapy resistance associated protein expression and activity, especially involved in the regulation of cell cycle checkpoint, apoptosis, DNA damage and repair, to clarify the molecular mechanisms of GDF15 in affecting chemosensitivity of OC. This study will not only help further elucidate the regulatory mechanism of chemotherapy resistance in OC, and also may provide an effective marker for predicting chemosensitivity in clinical settings and individualized treatment, furthermore, provide theoretical guidance for the development of GDF15-based sensitizing chemotherapy.

卵巢癌术后易复发，化疗抗拒是影响卵巢癌患者预后的一个重要原因。转化生长因子15(GDF15)是一种细胞外泌的TGF-β超家族细胞因子，我们前期研究证实卵巢癌细胞高表达GDF15并分泌至细胞外发挥细胞因子的调控作用，卵巢癌患者血清GDF15水平升高与患者无瘤进展生存及化疗耐药显著相关；组学研究发现GDF15影响卵巢癌细胞对化疗药物的敏感性可能主要涉及Akt信号通路。本课题拟从GDF15调节Akt信号通路为切入点，研究GDF15调控Akt活性的中间步骤，以及Akt激酶下游与化疗抗拒相关的蛋白表达和活性改变，尤其是参与细胞周期检测、细胞凋亡调控和DNA损伤及修复相关蛋白，阐明GDF15影响卵巢癌细胞化疗敏感性的分子机制。本课题不仅有助于阐明卵巢癌细胞对化疗药物抗拒的调控机制，而且可能为临床预测肿瘤化疗敏感性及个体化治疗提供一个有效的标志物，并为开发以GDF15为靶点的化疗增敏治疗提供理论基础。

卵巢癌术后易复发，化疗抗拒及肿瘤转移是影响卵巢癌患者预后的重要原因。转化生长因子15(GDF15)是一种细胞外泌的胶质源性神经营养因子的超家族分子，以往研究表明GDF15与肿瘤的发生发展密切相关。在本项目中，我们通过临床样本验证、表型实验鉴定及机制探讨三方面证实了GDF15通过激活PI3k/Akt通路进而促进能量代谢及脂质合成代谢进而调控卵巢癌化疗拮抗及肿瘤转移。卵巢癌患者血清中、肿瘤组织中GDF15水平升高与患者肿瘤转移、预后及化疗耐药显著相关，组学研究提示并实验验证了PI3k/Akt通路的激活是GDF15影响卵巢癌恶性表型的关键节点，能量代谢的上调及脂质合成代谢的促进是GDF15促进卵巢癌发展的重要因素。结合以上结果，本项目一定程度上阐明了GDF15调控化疗药物抗拒及肿瘤转移的具体分子机制。本项目不仅有助于阐明卵巢癌细胞对化疗药物抗拒及肿瘤转移的调控机制，而且可能为临床诊断和临床预测肿瘤化疗敏感性及个体化治疗提供一个有效的标志物，并为开发以GDF15为靶点的个性化治疗提供理论基础。