子宫内膜癌SIRT1-FoxO1-SREBP1信号通路的作用及孕激素抵抗相关机制的研究

In recent years, there has been an increasing incidence of the endometrial cancer as well as patients with resistance to progestin therapy and since the mechanism is unknown, there is a significant challenge in the scope of clinical therapy. Studies show that progesterone has a therapeutic role in endometrial cancer. It has been postulated that Silent Information Regulator1(SIRT1) acts on the progestin receptor (PR) and thereby regulates the function and location of PR. Meanwhile PR can activate Forkhead box O1(FoxO1) so as to indirectly repress Sterol Regulatory Element Binding Protein1(SREBP1) thus regulating downstream factors involved in lipid metablism. Our study primarily deals with defining the relationship between SIRT1-FoxO1-SREBP1 associated abnormal signaling pathway of lipid metablism in the development as well as prognosis of endometrioid adenocarcinoma through expanding the amount of tissue samples and a variety of functional experiments in vivo and in vitro. Then by establishing a stable cell line with progestin resistance, we attempt to detect the change in SIRT1-FoxO1-SREBP1 signaling pathway. We also explore the possibility of reversing the progestin resistance by interfering with the abnormal SIRT1-FoxO1-SREBP1 signaling pathway through in vivo and in vitro experiments. Consequently we try to reveal the associated mechanism of progestin resistance and provide new insights with theoretical basis towards the remedy aiming to improve progestin resistance in order to overcome the clinical dilemma which exists at the present.

近年来子宫内膜样腺癌发病率上升，孕激素治疗抵抗患者日渐增多，确切机制不明，给临床治疗带来巨大挑战。研究发现孕激素主要通过孕激素受体起治疗作用，而沉默信息调节因子1（SIRT1）可作用于PR，调节PR功能和定位，同时PR可激活叉头蛋白转录因子1（FoxO1），间接抑制固醇调节原件结合蛋白1（SREBP1），进而调节下游脂质代谢相关因子。本研究拟通过扩大组织标本量检测及多种体内外功能实验明确SIRT1- FoxO1-SREBP1介导的脂代谢异常信号通路与子宫内膜样腺癌发生发展和预后的相关性；诱导建立孕激素抵抗的稳定细胞系，监测SIRT1- FoxO1-SREBP1信号通路的变化，对异常SIRT1- FoxO1-SREBP1信号通路进行相应的干预，通过体内外实验探索能否逆转孕激素抵抗，从而揭示孕激素抵抗的相关机制，为进一步研发逆转孕激素抵抗的药物提供理论依据，解决临床孕激素抵抗难题。

近年来子宫内膜样腺癌发病率上升，孕激素治疗抵抗患者日渐增多，确切机制不明，给临床治疗带来巨大挑战。研究发现孕激素主要通过孕激素受体起治疗作用，而SIRT1可作用于PR，调节PR功能和定位，同时PR可激活FoxO1，间接抑制SREBP1，进而调节下游脂质代谢相关因子。本研究拟通过扩大组织标本量检测及多种体内外功能实验明确SIRT1- FoxO1-SREBP1介导的脂代谢异常信号通路与子宫内膜样腺癌发生发展和预后的相关性；诱导建立孕激素抵抗的稳定细胞系，监测SIRT1-FoxO1-SREBP1信号通路的变化，对异常SIRT1- FoxO1-SREBP1信号通路进行相应的干预，通过体内外实验探索能否逆转孕激素抵抗，从而揭示孕激素抵抗的相关机制。大样本临床组织免疫组化结果显示SIRT1在子宫内膜样腺癌、子宫内膜不典型增生及正常内膜组织的细胞核中高表达，阳性表达率分别为81.5%、54.2%、47.1%，且表达水平与组织分化程度，临床病理分期，有无淋巴结转移呈正相关，与患者总体生存率呈负相关。FOXO1 在正常内膜、不典型增生和子宫内膜样腺癌组织中的阳性表达率分别为90%、85%、45.07%，且表达水平与组织分化程度、临床病理分期，淋巴结转移情况呈负相关，与年龄无关，RT-PCR结果在mRNA水平上验证了这一点。进一步通过表达载体和RNA干扰技术及体内外实验显示敲除SIRT1或过表达FOXO1后可抑制SREBP1表达，抑制子宫内膜癌发生发展，证实SIRT1- FoxO1-SREBP1介导脂代谢异常参与子宫内膜样腺癌发生发展的作用机制。在孕激素抵抗的细胞系中发现SIRT1、SREBP1表达明显高于子宫内膜癌细胞系，FOXO1，PR明显低于子宫内膜癌细胞系，敲除SIRT1后不仅抑制SREBP1表达，而且促进FOXO1，PR表达，逆转了子宫内膜癌孕激素抵抗，为进一步研发逆转孕激素抵抗的药物提供理论依据，解决临床孕激素抵抗难题。