卵巢癌病死率居妇科恶性肿瘤之首，顺铂耐药是上皮性卵巢癌化疗失败的主要原因。我们的基因表达谱芯片结果表明靶向抑制卵巢癌Gli基因后多药耐药基因MDR1表达下降。鉴于卵巢癌耐药株Hh信号通路成员SHH、Gli2及MDR1基因表达量及蛋白表达量均显著高于亲本株，用N-Shh刺激或过表达Gli2基因使MDR1上调而DNA损伤标志分子γH2AX下降，Cyclopamine 抑制Hh信号通路或沉默Gli2基因后得到相反的结果且卵巢癌细胞对顺铂的IC50值明显下降（见前期工作基础），本项目拟建立相应的细胞模型和选择性卵巢Gli2基因敲除动物模型，综合染色质免疫共沉淀、荧光素酶报告基因实验和基因定点突变实验等技术，从分子水平、细胞水平、临床水平及动物实验等多个层次发掘Gli2对MDR1的直接调控作用，探索靶向Gli2逆转卵巢癌顺铂耐药特性的分子机制，为耐顺铂上皮性卵巢癌的靶向治疗策略提供理论依据及新思路。

Ovarian cancer is the most lethal cause of death from gynecologic malignancies. The most important factor of ovarian cancer chemotherapy failure mainly due to cisplatin resistance. Early gene chip analysis demonstrated that the expression of MDR1, a multidrug resistance gene, decreased after targeting Gli in ovarian cancer cell line. The gene and protein expression of HH pathway components (SHH, Gli) and MDR1 in cisplatin-resistant ovarian cancer cell line are significantly higher than ordinary ovarian cancer cell line. MDR1 was up-regulated while DNA damage marker γH2AX was decreased after N-Shh treatment or overexpression of Gli2 in ovarian cancer, the result reversed due to inhibition of HH with cyclopamine or knockdown of Gli2, furthermore The IC50 value of cisplatin in ovarian cancer cells (ES-2) was significantly decreased after inhibiting the HH pathway (results are presented on the Foundation of preliminary work). Overall, In the present application, our group will develop the corresponding cell model, animal model of Knockout Gli2 only in the ovaries, and the chromatin immunoprecipitation, luciferase experiment and gene site-directed mutagenesis methods will be applied to reveal the direct regulation effect of Gli2 on MDR1 at molecular level, cellular level, clinical level and animal level, and explore the molecular mechanism of Gli2 reversing the cisplatin resistance of ovarian cancer via targeting the Gli2 protein, which provide theoretical basis and new ideas for the targeted therapy of cisplatin-resistant ovarian cancer.