去泛素化酶USP5在p53突变型高级别浆液性卵巢癌中的作用机制研究

卵巢癌（Ovarian cancer）作为一种高度异质性肿瘤，大多数卵巢癌被发现时已经是中晚期，死亡率居妇科恶性肿瘤之首。高级别浆液性卵巢癌（HGSOC）是卵巢癌中最常见也是恶性程度最高的亚型，占所有卵巢癌死亡率的80%。96%的HGSOC存在p53基因突变。前期研究发现，HGSOC中去泛素化酶USP5的表达受R248Q突变型p53调控，USP5还可以上调HDAC2/3的表达并参与对顺铂的耐药。本课题拟进一步研究（1）p53 R248Q突变调控USP5的分子机制；（2）USP5上调HDAC2/3促进HGSOC细胞恶性增殖的分子机制；（3）HGSOC高表达USP5对顺铂耐药的作用；（4）建立p53 R248Q突变的HGSOC小鼠PDOX模型，探讨通过小分子化合物抑制USP5和HDAC2/3活性，发挥抑制卵巢癌增殖和增加对顺铂治疗的敏感性。

Ovarian cancer is one of the highly heterogeneous malignancies. Most of ovarian cancers are detected during the middle and advanced stages leading to the highest mortality rate among gynecological malignancies. High-grade serous ovarian cancer (HGSOC) is the most common and aggressive histologic subtype of ovarian cancer, accounting for 80% of all ovarian cancer mortalities. 96% of HGSOCs harbor p53 gene mutations. Our previous studies revealed that the expression of the deubiquitinase USP5 in HGSOCs is regulated by p53 protein with R248Q mutation. USP5 can also up-regulate the expression of HDAC2 and HDAC3 and participate in the resistance to cisplatin. In this project, we intend to further investigate the following subjects: (1) the underlying mechanism of p53 R248Q mutation in regulation of USP5 expression; (2) the role of USP5 in HGSOC cells proliferation through up-regulating HDAC2 and HDAC3; (3) the molecular function of high expression level of USP5 in cisplatin resistance in HGSOCs; (4) to establish p53 R248Q mutant HGSOC mouse PDOX model and to explore the effect of small molecule inhibitors of USP5, HDAC2 and HDAC3 on HGSOC cell proliferation and sensitivity to cisplatin treatment.