FSH对子宫内膜癌的调控及AMPK介导的分子机制

Endometrial cancer is the most common malignancy among malignant female genital tumors, and its mortality rate is the third among gynecologic cancers. Recently, extragonadal roles of FSH (Follicle-stimulating hormone) is increasingly valued by the researchers, especially in regulating tumor formation and development. Studies show that FSH is relevant to endometrial cancer, but no research on the detailed mechanism has been found reported. Our previous study proved that FSH inhibited AMPK activity via FSHR and impaired glucose metabolism. Impaired glucose metabolism is one major risk factor for endometrial cancer. We hypothesized that FSH impacted the formation and development of endometrial cancer via AMPK signaling. This study takes FSH as the starting point, combines clinical trial (analyzing the relationship between serum FSH and endometrial cancer, endometrium specimen), in vivo study (tumor xenograft mice model, ovariectomized mice supplemented with E2) and in vitro study (FSH treatment, gene overexpression and silence, CHIP, Luciferase assay), and illuminates FSH regulates endometrial cancer through AMPK. Our study will provide newly theoretical evidence for pathogenesis and clinical treatment of endometrial cancer.

子宫内膜癌是最常见的女性生殖系统肿瘤之一，并是导致死亡的第三位常见妇科恶性肿瘤。近年来FSH（卵泡刺激素）的性腺外作用越来越多地被重视，尤其在调控肿瘤发生发展方面。研究表明FSH与子宫内膜癌相关，但详细机制未见报道。在前期工作中，我们发现FSH可以通过FSHR抑制AMPK的活性，促进糖代谢异常的发生。而糖代谢异常是子宫内膜癌的危险因素。据此我们推测FSH可通过AMPK及相关通路影响子宫内膜癌的发生发展。本项目由FSH切入，拟采用临床实验（分析人血清FSH水平与子宫内膜癌的关系，人子宫内膜标本）、体内实验（移植瘤小鼠模型，双侧卵巢去势补充雌激素小鼠等多种动物模型）和体外实验（FSH刺激子宫内膜癌细胞，基因沉默和过表达，染色质免疫共沉淀，荧光素酶报告基因等技术）相结合的方法，阐明FSH通过AMPK对子宫内膜癌的调控作用，为子宫内膜癌病因研究及治疗进展提供新的思路和理论基础。

作为子宫内膜癌的危险因素，内分泌干扰物与血清卵泡刺激素(FSH)水平呈正相关。此外，FSH水平升高与子宫内膜癌相关。然而其确切机制尚不清楚。因此，本研究探讨FSH如何影响子宫内膜癌的发生发展。通过免疫组化(IHC)、免疫荧光(IF)和Western blot(WB)检测，我们发现FSH受体(FSHR)在子宫内膜癌组织和细胞系中均有表达。为了探索FSH在体外对子宫内膜癌细胞的影响，在不同剂量的FSH下培养Ishikawa (ISK)细胞，发现FSH能促进ISK细胞的增殖和迁移。此外，通过WB检测迁移、侵袭和凋亡关键分子，我们发现FSH可以促进细胞的迁移和侵袭，抑制细胞凋亡。而且，FSH可以抑制AMPK的活性。为了阐明FSH在体内对子宫内膜癌的影响，我们构建了双侧卵巢去势并补充雌激素（目的为排除注射FSH后对体内雌激素的影响）的皮下移植瘤裸鼠模型。与OE(双侧卵巢去势并补充雌激素)组和假手术组相比，OE+FSH组肿瘤的生长速度更快，重量明显更高。以上结果提示FSH促进子宫内膜癌的发生与发展。本研究提出了子宫内膜癌新的可能的发病机制，为临床治疗子宫内膜癌提供了新的思路和策略，具有重要的理论价值和临床意义。