线粒体自噬在宫颈癌发生中的作用及机制研究

宫颈癌属于妇科常见恶性肿瘤之一。新近研究表明线粒体自噬与宫颈癌发生关系极为密切，但相关作用及分子机制并不明确。预实验结果显示宫颈癌组织内parkin依赖的线粒体自噬水平较低，可能与癌组织中异常表达的组蛋白去乙酰化酶引起的乙酰化parkin低表达有关，深入研究发现乙酰化parkin可能通过泛素化降解GAPDH而抑制宫颈癌生长，但仍需进一步探讨。我们假设乙酰化parkin通过线粒体自噬性降解GAPDH而发挥抗宫颈癌效应。本课题拟通过分析GAPDH泛素化位点，明确parkin泛素化降解GAPDH的分子机制；通过细胞学、动物模型等实验，验证parkin-GAPDH通路通过影响能量代谢而抑制宫颈癌生长；同时分析宫颈癌组织中parkin、GAPDH等线粒体自噬蛋白表达与患者临床特征及预后的相关性。通过本课题的实施，有助于明确线粒体自噬在宫颈癌发生中的作用及重要性，并为宫颈癌治疗提供新的靶点和实验依据。

Cervical cancer is one of the most common gynecological malignancies. Recent studies have shown that mitophagy is closely related with cervical cancer, but the role and molecular mechanism are not clear. Our preliminary data showed that in cervical cancer tissues, the levels of parkin-dependent mitophagy was very low, which may be associated with the lower acetylation level of parkin due to abnormal expression of histone deacetylase in cervical cancer. Further study demonstrated that the acetylated parkin may inhibit the growth of cervical cancer through degradation of GAPDH, but more study is needed. Here, We hypothesized that the acetylated parkin exerts the anti-cervical cancer effect through mitophagic degradation of GAPDH. We intend to identify the molecular mechanism of parkin-dependent degradation of GAPDH by analyzing the ubiquitination sites of GAPDH. Cytological experiments and animal work were conducted to verify that the parkin-GAPDH pathway inhibits the growth of cervical cancer by regulating energy metabolism. Meanwhile, the correlation between the expression of mitophagy-related proteins such as parkin and GAPDH in cervical cancer tissues and the clinical characteristics and prognosis of patients was also analyzed. Through the implementation of this project, it is helpful to clarify the role and importance of mitophagy in the tumorigenesis of cervical cancer, providing a novel target and experimental basis for the treatment of cervical cancer.