FOXO1-自噬通路异常在雌、孕激素失调诱发的子宫内膜样腺癌中作用机制的研究

Endometrioid adenocarcinoma is an oestrogen-dependent, non-progesterone antagonistic neoplasia, of which incidence is high and the mechanism is still obscure. By employing high-throughput tissue RNA-array screening, we identify transcription factor FOXO1, as well as its down-stream targets including IGFBP1 and GADD45, are highly expressed in early stage, whereas depleted in late stage of endometrioid adenocarcinoma. Our previous finding indicates that FOXO1 negatively regulates cell proliferation by inducing autophagy in certain type of cancer cells, and FOXO1 is significantly down-regulated upon treatment with oestrogen combined with progesterone withdrawal. To further assess the potential role of FOXO1 in endometrioid adenocarcinoma development in oestrogen/progesterone imbalance condition, we plan to make autophagy as a breakthrough point in current research. Research plan: 1) To compare mutation status and posttranslational modification alteration of FOXO1 between early stage and late stage tissue samples in a large scale. 2) To explore the effect of oestrogen and progesterone on FOXO1 per se and FOXO1-mediated autophagy. 3) To evaluate whether a correlation exists between FOXO1-mediated autophagy and developmental progress of endometrioid adenocarcinoma. The study aims to investigate more detail of the molecular mechanism and provide potential targeting therapeutic strategy in endometrioid adenocarcinoma.

子宫内膜样腺癌是雌激素依赖非孕激素拮抗性肿瘤，发病率高，但其发病的分子机制仍不清。本课题组前期用组织芯片技术发现转录因子FOXO1及其下游靶基因（IGFBP1，GADD45等）在高分化、早期子宫内膜样腺癌中高表达；而在低分化、晚期子宫内膜样腺癌中低表达。实验结果显示，FOXO1通过促进细胞自噬抑制肿瘤细胞生长，孕激素缺乏合并高雌激素刺激下调FOXO1的表达。本研究拟以细胞自噬为切入点探讨雌、孕激素失调诱发因素下FOXO1-自噬通路的异常改变及其对子宫内膜样腺癌发生发展的影响。研究内容：1）检测不同分化程度子宫内膜样腺癌中FOXO1是否存在基因水平突变和翻译后修饰改变。2）检测雌/孕激素水平波动对FOXO1及FOXO1介导的细胞自噬的影响。3）探讨FOXO1是否通过调控细胞自噬影响子宫内膜样腺癌的发病、侵袭和转移。旨在为子宫内膜样腺癌发病分子机制和分子靶向治疗提供基础。

子宫内膜样腺癌是雌激素依赖非孕激素拮抗性肿瘤，本项目研究了FOXO1在子宫内膜样腺癌发生、发展中的作用，并探讨了子宫内膜癌的危险因素对FOXO1的影响及FOXO1调控子宫内膜样腺癌的发生、发展的分子机制，发现雌激素-FOXO1-自噬通路是子宫内膜癌发生的保护因素；在雌激素持续长期作用下，MAPK通路激活导致内膜癌细胞异常增生，DUSP1酶活性反馈性上调，抑制FOXO1磷酸化，使FOXO1入核、从而抑制自噬，导致子宫内膜癌的发生。为子宫内膜样腺癌的发病机制提供更完善的资料，为子宫内膜样腺癌的诊断和治疗提供积极有效的理论依据。