Id1因子在卵巢癌小鼠内皮祖细胞动员和归巢中的作用和相关机制

Because of the characteristics of prone to metastasis of ovarian cancer, it is very difficult to get satisfactory outcome. Recently, angiogenesis is widely considered as a major factor resulting in metastasis of ovarian cancer, moreover, endothelial progenitor cells (EPCs) involve in tumor angiogenesis. In previous study, we observed higher level of EPCs in peripheral blood of patients with oviarian cancer than that in peripheral blood of health volunteer, moreover, Id1 expression were increased in EPCs freshly isolated from ovarian cancer patients compared to those obtained from healthy volunteer. siRNA-mediated Id1 downregulation substantially reduced EPCs function. On the basis of these results, we hypotheses that mechanism that EPCs promote progress and metastasis of ovarian cancer may be correlated with Id1. The present study aimes to investigate how Id1 affect biological function of EPCs in the model of nude mice with ovarian cancer in vivo and ex vivo. We explore that effect of Id1 on mobilization and homing of EPCs based on the living imaging system. In addtion, we also study the effect and mechanism of Id1 on progress and metastasis of ovarian cancer. To date we have no found any an report with regards to Id1 mediated EPCs angiogenesis and metastasis of ovarian cancer, so the study will not only provide a novel theory about angiogenesis of ovarian cancer, but will bring a new strategy or target for improving outcome of ovarian cancer by the means of attenuating effect of EPCs.

卵巢癌转移是造成治疗困难的主要原因，而血管新生是卵巢癌转移的主要机制，血管内皮祖细胞（EPCs）参与肿瘤的血管新生。前期研究发现，卵巢癌患者外周血中EPCs水平较健康人显著升高，并且EPCs上分化抑制因子1(Id1)高表达及Id1增强EPCs的生物学功能等研究结果基础上，提出EPCs促进卵巢癌血管新生及生长转移的机制与Id1有关的假设。本课题拟进一步于在体和离体裸鼠卵巢癌模型上，观察Id1对卵巢癌EPCs的生物学功能的影响及机制；并基于活体成像系统观察Id1对卵巢癌EPCs的动员和归巢的影响，观察Id1对卵巢癌的生长和转移的作用及其作用机制，获得其和体外一致结果的证据。由于Id1在EPCs促进卵巢癌血管新生和转移中作用及机制研究目前尚无文献报道，因此本课题研究具有源头创新性。研究若成功，将为卵巢癌血管新生的机制提供新理论，为EPCs致卵巢癌生长和转移的早期防治提供新线索和潜在的干预靶标。

卵巢癌是妇科常见恶性肿瘤之一，其发病率居妇科肿瘤第三位。然而卵巢癌的死亡率高居妇科肿瘤首位，5年生存率仍然徘徊在30%左右。卵巢癌浸润、转移是造成卵巢癌治疗困难的主要原因，内皮祖细胞（EPCs）参与肿瘤的血管新生，促进肿瘤生长已经得到了证实。故EPCs与肿瘤的生长转移密切相关，但EPCs与卵巢癌的生长与转移关系还未见报道。分化抑制因子1(Id1)表达于骨髓来源的EPCs，Id1可介导EPCs的生物学功能来促进肿瘤的发生和发展。但Id1对卵巢癌EPCs具体的生物学功能的影响尚不十分清楚。本研究发现：1.Id1在卵巢癌EPCs上高表达；2.Id1过表达慢病毒载体可导致EPCs增殖、粘附、迁移和血管生成的功能增强；3.Id1沉默表达慢病毒载体可导致EPCs增殖、粘附、迁移和血管生成的功能减弱；4.转染Id1的EPCs诱导AKT的磷酸化并且通过NF-KB来增加MMP-2的表达；5.给予PI3K信号通路阻断剂LY294002，发现EPCs的增殖、粘附、迁移和血管生成功能受到抑制；6.给予NF-KB的阻断剂PDTC，发现EPCs的增殖、粘附、迁移和血管生成功能受到抑制；7.Id1促进EPCs的增殖、粘附、迁移和血管生成，并且和PI3K/AKt以及NF-KB/MMP-2这两条信号通路有关。8. EPCs和卵巢癌细胞共培养后，可诱导增强卵巢癌细胞的迁移能力。9. EPCs诱导卵巢癌细胞的上皮间质转化作用。10.内皮祖细胞通过分泌TGF-β来作用于卵巢癌细胞的。11.TGF-β在EPCs诱导卵巢癌细胞的迁移和上皮间质转化中发挥作用。本课题通过研究，对Id1致使EPCs生物学功能的影响增进了人们对卵巢癌生长和转移分子机制的新认识；若能够进一步深入分析Id1在卵巢癌、EPCs生物学功能与机制，将有助于了解EPCs参与卵巢癌生长和转移的分子机制，并可能为卵巢癌的发生防治提供新的靶标，对卵巢癌的防治药物研发提供帮助，因此有着潜在的经济价值与良好的社会意义。