糖代谢异常通过激活内质网IP3R释放钙离子调控子宫内膜癌增殖与侵袭的分子机制研究

Metabolic syndrome with a triad of obesity, hypertension and diabetes is commonly observed in endometrial carcinoma cases. Studys found the incidence of endometrial carcinoma is closely related to metabolic disorders. Our project team early results show that insulin and insulin-like growth factor involved in proliferation and apoptosis of endometrial carcinoma cell, and calcium and its channel promote proliferation and invasion of endometrial cancer cell. There is no reports about whether calcium and its channel are associated with glycometabolism disorder in endometrial carcinoma.This project will research the following four aspects: (1) researching the influence of glucose and insulin on proliferation and invasion of endometrial carcinoma;(2) researching the influence of glucose and insulin on intracellular Ca2+ levels;(3) researching whether glucose and insulin influence intracellular Ca2+ levels through PKA ( cAMP-Dependent Protein Kinase)activating Ca2+ releasing channel IP3R(Inositol 1,4,5-Trisphosphate Receptor) located on endoplasmic reticulum;(4)researching whether blocking/enhancing PKA-IP3R-Ca2 + changes the influence of glucose and insulin on proliferation and invasion of endometrial carcinoma cell.The main purposes of this project are:(1)providing a new idea of study the relationship between endometrial carcinoma and glycometabolism disorder through glycometabolism disorder connecting to Ca2+ and its channel;(2) Providing experimental and theoretical basis for further study of personalized treatment for hyperglycemia endometrial cancer cases.

临床上肥胖-高血压-糖尿病统称为“子宫内膜癌三联征”。研究发现内膜癌发病与代谢紊乱密切相关。课题组前期研究表明，胰岛素和胰岛素样因子参与子宫内膜癌细胞增殖和凋亡，Ca2+及其通道可以上调内膜癌细胞增殖和侵袭。是否Ca2+及其通道与子宫内膜癌糖代谢异常存在关联？目前尚未见报道。本项目拟从以下4个方面进行研究: (1)研究葡萄糖、胰岛素对内膜癌细胞增殖、侵袭的影响；(2)研究葡萄糖、胰岛素对细胞内Ca2+水平的影响；(2)研究葡萄糖、胰岛素对细胞内Ca2+水平的影响是否通过PKA激活内质网Ca2+释放通道IP3R；(4)阻断/增强PKA-IP3R-Ca2+是否改变葡萄糖、胰岛素对内膜癌细胞增殖与侵袭的影响。主要目的：研究糖代谢异常通过Ca2+及内质网上IP3R影响内膜癌增殖和侵袭的机制，为研究内膜癌与糖代谢紊乱的关系提供新路思路，为下一步研究高血糖内膜癌病例个性化治疗提供实验及理论基础。

子宫内膜癌与糖尿病、肥胖和高血压密切相关，临床上将肥胖-高血压-糖尿病统称为“子宫内膜癌三联征”。研究发现子宫内膜癌发病与代谢紊乱密切相关，但具体关联机制仍然不清。本课题基于前期研究发现胰岛素及胰岛素样生长因子在调控子宫内膜癌细胞增殖和凋亡中的作用，以及Ca2+信号及其通道在调控子宫内膜癌进展中的作用，旨在进一步探索糖代谢异常通过Ca2+及内质网IP3R影响内膜癌增殖和侵袭的机制。通过系列细胞实验和分子生物学实验，本项目研究发现高浓度葡萄糖促进子宫内膜癌增殖和侵袭，胰岛素促进子宫内膜癌糖摄取过程。初步证实了，胰岛素可导致内质网应激，子宫内膜癌细胞内Ca2+降低和线粒体内Ca2+升高。进一步发现胰岛素促进子宫内膜癌细胞ROS的生成和DNA损伤发生，并通过磷酸化蛋白质芯片筛选明确了胰岛素对下游p70S6K信号通路的调控作用。此外，基于临床样本信息数据和TCGA数据库的综合分析提示，血钙可能是评估子宫内膜癌患者代谢综合征的一个新的指标，糖脂代谢异常可能通过影响Ca2+信号协同调控子宫内膜癌的发生和发展。本项目的研究为糖代谢相关的子宫内膜癌的预防和个性化靶向治疗提供了新的思路和实验依据。