子宫内膜样腺癌（Endometrial adenocarcinoma，EAC）发病率逐年增加，日益年轻化，孕激素是年轻EAC患者保留生育功能的主要治疗手段，然逾30%患者对孕激素不敏感或在治疗过程中产生孕激素抵抗，具体机制不清。研究表明SREBP1可通过调节脂代谢在恶性肿瘤中发挥促癌作用。前期证实SREBP1可促进EAC的发生发展，我们在建立的孕激素抵抗细胞株（Ish/MPA）中发现SREBP1，YAP/TAZ，MAGL一致高表达，敲除SREBP1可改善Ish/MPA细胞株对孕激素的敏感性，下调YAP/TAZ及MAGL，初步表明SREBP1通过YAP/TAZ及MAGL增强细胞增殖迁移能力，促进细胞在孕激素治疗下的生存，诱发孕激素抵抗。本课题拟通过基因干扰、双荧光素酶报告、裸鼠移植瘤等体内外实验研究SREBP1介导Hippo通路调控MAGL与孕激素抵抗的相关机制，以期解决临床孕激素抵抗问题。

The incidence rate of endometrial adenocarcinoma (EAC) is constantly growing, and the age of onset is the trend of younger. High-dose progesterone is an effective endocrine treatment for young EAC patients with the demand of preserving fertility. However, up to 30 percent of patients are not sensitive to progesterone or develop resistance to progesterone during the treatment. And the concrete mechanisms are not clear. Some studies have shown that sterol regulatory element binding protein 1(SREBP1), which is highly expressed in many human malignancies, acts as an oncogene by regulating lipids metabolism. We found that the overexpression of SREBP1 enhances the occurrence and development of EAC, while SREBP1, YAP/TAZ and MAGL all strongly express in progesterone-resistant Ishikawa cells which have been successfully established during preliminary experiment. Inversely, inhibition of SREBP1 renders progesterone-resistant Ishikawa cells more susceptible to progesterone treatment, following the down regulation of YAP/TAZ and MAGL. We hypothesized that the overexpression of SREBP1 promotes the proliferation and migration of progesterone-resistant Ishikawa cells by upregulating YAP/TAZ and MAGL expression. In this study, knocking down or overexpressing SREBP1 in EAC cells, luciferase assay and nude mice xenograft model etc. will be performed to further explore the mechanisms of MAGL regulated by SREBP1 through hippo pathway in progesterone resistance development. It may provide potential therapeutic targets for the treatment of young EAC patients with progesterone resistance.