胰岛素抵抗相关脂肪因子及二甲双胍对子宫内膜癌细胞生长影响信号通路的探讨

Endometrial cancer is the most common gynecological malignancy, accounting for 6% of all cancers in women. However, a subset of young women in a setting of type 2 diabetes, obesity, polycystic ovarian syndrome is in the high risk of developing endometrial cancer. Their common pathophysiological basis is insulin resistance. But its mechanism is still unknown. A recent case report has shown that combination therapy with metformin and oral contraceptives may reverse progesterone resistant typical endometrial hyperplasia, but this mechanism is unclear. Our preliminary studies have shown that metformin can significantly inhibit the growth of endometrial cancer cells, but its molecular mechanism is worth to explore deeply...This objective of this study is to detect the influence of insulin resistance related adipokines such as adiponectin, leptin, visfatin and resistin on the expression of estrogen and progesterone receptors, insulin growths factor systems and glucose metabolism-related factors and PI3K/AKT, AMPK, mTOR signaling pathway in endometrial cancer cells, which is the downstream signaling pathways in the growth inhibition effects of metformin on endometrial cancer cells and its impact on the insulin resistance related adiopkines. We try to understand the impact of insulin resistance in the endometrial hyperplasia and atyical hyperplasia in the animal models, to investigate insulin resistance in the pathogenesis of endometrial hyperplasia and cancer, and to find out the possible mechanisms and links between metformin and the antiproliferative effect on the endometrial carcinoma cells. ..We aim to confirm metformin or other drugs to reduce the occurrence of endometrial dysplasia in the premenopausal obese women, evaluate the safety and feasibility of metformin in the treatment of endometrial cancer. By looking for the susceptibility of prognosis,a further improvement in the prognosis of patients with endometrial cancer might be achieved.

胰岛素抵抗、肥胖是Ｉ型子宫内膜癌的高危因素，其机制不明，临床工作中胰岛素增敏剂可提供孕激素对子宫不典型增生和早期内膜癌的疗效。我们的前期研究显示二甲双胍可以显著抑制子宫内膜癌细胞的生长，但其作用的分子机制值得深入研究。本课题通过检测胰岛素抵抗相关脂肪因子（脂联素、瘦素、内脂素、抵抗素）对子宫内膜癌细胞雌、孕激素受体、IGFs、糖代谢相关因子、mTOR信号通路之间的影响；二甲双胍对子宫内膜癌细胞脂肪因子及下游信号通路的影响；通过建立胰岛素抵抗的子宫内膜过度增生和子宫内膜癌的动物模型检测胰岛素抵抗对于子宫内膜的影响。探讨胰岛素抵抗相关脂肪因子与子宫内膜过度增殖和子宫内膜癌发病的关系、及二甲双胍对子宫内膜癌细胞抗增殖作用可能机制与环节。以期寻找减少绝经前肥胖妇女子宫内膜异常增生发生的药物；验证二甲双胍治疗子宫内膜癌的安全性和可行性；寻找疗效判断新的靶点，从而使内膜癌患者的预后得到更进一步的改善。

向心性肥胖、2型糖尿病、多囊卵巢综合症是I型子宫内膜癌发生的高危因素，其共同的病理生理基础是胰岛素抵抗和继发的高胰岛素血症，后二者在子宫内膜增生病变和子宫内膜癌的发展中起着重要作用。研究明确胰岛素抵抗相关脂肪因子在子宫内膜癌人群中的变化及与临床预后的关系；检测脂肪因子对于子宫内膜癌细胞生长的影响，建立胰岛素抵抗的子宫内膜过度增生动物模型，检测胰岛素抵抗对于子宫内膜的影响；探讨胰岛素抵抗与子宫内膜过度增殖和子宫内膜癌的关系、二甲双胍抑制子宫内膜癌细胞增殖作用的机制。结果：1.与对照组相比，子宫内膜癌和非典型增生患者的瘦素和抵抗素水平均明显升高，脂联素水平明显降低。2.抵抗素促进HEC和IK两种子宫内膜癌细胞系的生长，呈时间和浓度依赖性；抵抗素促进两种子宫内膜癌细胞系中PI3K/Akt信号通路的激活。3.脂联素抑制子宫内膜癌细胞系的增殖，二甲双胍和脂联素有协同抗增殖作用，呈时间和浓度依赖性。二甲双胍促进子宫内膜癌细胞系脂联素受体的表达，并通过AMPK通路参与调控。4.高脂饮食诱导SD大鼠出现胰岛素抵抗，雌激素诱导大鼠子宫内膜增殖及鳞化。伴有胰岛素抵抗的大鼠子宫内膜增殖表现更显著，主要表现在子宫腔上皮和腺上皮细胞的高度增大以及子宫内膜的鳞化比例升高。5.胰岛素抵抗大鼠发生子宫内膜增殖时血浆和子宫组织中脂联素水平下降、瘦素水平升高，子宫组织PTEN的表达减少，AMPK和PI3K/Akt信号传导通路被激活。脂肪因子的异常表达和子宫内膜异常增殖及癌变有密切关系。脂联素抑制子宫内膜癌细胞增殖和侵袭，二甲双胍和脂联素对于子宫内膜癌细胞系有协同抗增殖作用，抵抗素则可促进其增殖和侵袭。构建胰岛素抵抗和子宫内膜增殖大鼠模型为高胰岛素环境对子宫内膜增殖病变提供实验依据。胰岛素抵抗和子宫内膜增殖实验动物和临床子宫内膜癌患者体内脂联素和瘦素均呈明显的变化，AMPK和PI3K/Akt信号通路被激活。胰岛素抵抗相关脂肪因子与子宫内膜癌的发生密切相关，为二甲双胍可能成为I型子宫内膜癌的新型辅助治疗药物提供理论和实验基础。对于年轻的代谢综合征患者，缓解胰岛素抵抗可改变体内脂肪因子的水平，对预防子宫内膜异常增殖及癌变有重要意义。对于肥胖的 I 型子宫内膜癌患者，改善其体内胰岛素抵抗，调节其体内脂肪因子水平，可能达到抑制子宫内膜癌细胞增殖、减少复发、改善子宫内膜癌患者预后的治疗价值。