雌激素通过CaSR激活钙流在子宫内膜癌脉管形成中的机制研究

The blood and lymphatic vessels have a significant impact on distant metastasis of the endometrial cancer, but the underlying mechanism is unclear and complex. Studies have shown that CaSR prompted to participate in the formation of tumor vessels. Our previous studies showed that the expression of CaSR and the Inward flow of calcium increased in endometrial cancer ishikawa cells after estrogen stimulation. In addition, overexpression of CaSR inhibits the expression of various VEGFs, and promotes the expression of ER, suggesting that CaSR and estrogen can be directly or indirectly involved in the vessel formation of endometrial carcinoma. Thus, we propose that CaSR can be transcriptionally modulated by estrogen which increased the external calcium influx and estrogen receptor expression in a positive feedback manner, and finally restrain the vessel formation in endometrial cancer. This project is proposed to further elucidate the intrinsic regulation mechanism between estrogen and CaSR，and clarified the regulatory effects of estrogen and CaSR in endometrial cancer vessel formation via Dorsal Skinfold Chamber model and orthotopically implanted model, which will provide a novel target for the prevention and reduction of endometrial cancer metastasis through vessel formation inhibition.

子宫内膜癌的远处转移主要通过脉管（血管或/和淋巴管），脉管的形成对肿瘤进展及预后中具有着重要影响，但其调控机制不明。研究表明CaSR可以参与肿瘤脉管的形成。我们前期发现，子宫内膜癌Ishikawa细胞给予雌激素刺激后CaSR表达增高，同时增加细胞外钙的内流。转染过表达CaSR抑制多种VEGF因子的表达，同时促进雌激素受体表达，暗示着CaSR和雌激素可直接或间接参与子宫内膜癌的脉管形成。由此，我们提出假设：雌激素可以通过转录作用诱导CaSR表达，CaSR增加外钙内流且正反馈雌激素受体表达，强化对子宫内膜癌脉管形成的抑制。本研究将延续前期研究结果，通过背皮褶室及原位移植瘤动物模型，阐明雌激素与CaSR之间的内在调控机制，揭示雌激素与CaSR调控子宫内膜癌脉管形成的现象，为寻找子宫内膜癌脉管形成的靶点奠定基础，为预防和减少子宫内膜癌的转移提供新思路。

子宫内膜癌的远处转移主要通过脉管（血管或/和淋巴管），脉管的形成对肿瘤进展及预后中具有着重要影响，但其调控机制不明。研究表明CaSR可以参与肿瘤脉管的形成。在本究通过细胞实验、分子实验及动物实验三个方面的研究发现雌激素可以通过诱导CaSR表达，而CaSR增加正反馈雌激素受体表达，转染过表达CaSR抑制子宫内膜癌细胞血管及淋巴管的形成，沉默CaSR促进脉管形成，CaSR负性调控子宫内膜癌细胞脉管的形成。雌激素可促进CASR抑制脉管形成作用，使用钙离子通道抑制剂及钙螯合剂可部分逆转CASR作用。本研究揭示了CaSR可直接或间接抑制子宫内膜癌的脉管形成，以之为靶点的新型治疗途径，有望减少子宫内膜癌患者的发生、复发，提高患者的预后。