趋化因子受体CXCR2促进卵巢癌转移及特异性干预的分子机理研究

Ovarian cancer is one of the most common female malignancy and is the leading cause of death from gynecological malignancies．In clinical, ovarian cancer is characterize by invasion and metastasis, which are also the difficulties of treatment. So there is a urgent need for a better understanding of the mechanisms involved in the invasion and metastasis of ovarian carcinoma. some recent research indicated that, CXC chemokines receptor 2 and its ligands promoted the invasion, metastasis and cancer stem-like cells (CSCs) activities in several tumor cell lines. But the molecular mechanisms are not very clear. Our previous work showed that the invasion and migration of ovarian cancer cell lines HEY and HEY-A8 were decrease due to the shRNA dependent silence of CXCR2 expression or the treatment of small molecular antagonist of CXCR2. Moreover, It's also observed that Notch 3 signaling pathway was regulated by CXCR2, which may associate with the CSCs activities and CSCs dependent invasion and metastasis. Hence, in this study, the role of CXCR2 and its ligand IL-8, Gro-1 in the invasion and metastasis of ovarian cancer will be well defined and the molecular mechanism will be also investigated in vitro and in vivo. Move, the effect and mechanism of small molecular antagonist against the invasion and metastasis of ovarian will be also accessed. It is hopeful that this study would provide a solid foundation in the discovery of novel CXCR2-targeted anti-tumor therapies.

卵巢癌是严重威胁妇女生命和健康的疾病，死亡率居妇科肿瘤之首。其主要临床特征是侵袭、转移。因此，深入阐明卵巢癌侵袭转移的分子机制是提高其临床诊断和疗效的关键。近期研究发现趋化因子受体CXCR2及其配体推动了多种肿瘤的侵袭、转移以及肿瘤干细胞活性，但其机理却不十分清楚。本项目的前期工作表明在卵巢癌细胞系中沉默CXCR2，或者用CXCR2小分子拮抗剂处理可以降低肿瘤细胞的侵袭、转移。同时，CXCR2还可以调控Notch3信号通路，这可能与肿瘤干细胞及其介导的侵袭、转移相关。因此，本项目拟在前期工作的基础上，从细胞、动物水平研究CXCR2及其配体IL-8、Gro-1对卵巢癌侵袭、转移、干细胞样活性的影响，并进一步探讨具体的分子机制。同时研究CXCR2小分子拮抗剂在干预卵巢癌侵袭、转移的作用及机理，为研究开发靶向CXCR2的肿瘤靶向治疗打下实验室基础。

卵巢癌是女性生殖器官常见的恶性肿瘤之一，患者死亡率居妇科恶性肿瘤之首，严重威胁妇女的生命健康。卵巢肿瘤的侵袭、转移是有效治愈卵巢癌的最大障碍。因此，深入研究卵巢癌侵袭、转移相关的分子机制，针对侵袭、转移过程中的关键靶标，研究开发有效的肿瘤靶向药物具有十分重要的理论研究意义和临床应用价值。近年来，大量研究表明趋化因子受体CXCR2在多种肿瘤的形成、生长、侵袭、转移及预后中都具有重要作用。因此，本项目研究了CXCR2对卵巢癌侵袭、转移和上皮间质转化的影响。体外实验表明，沉默CXCR2的卵巢癌细胞，侵袭、迁移能力下降，EMT相关标志物E-cadherin表达上调，Vimentin、snail表达下调。过表达CXCR2的卵巢癌细胞，侵袭、迁移能力增强，EMT相关标志物E-cadherin表达下调，Vimentin、snail表达增高。信号通路检测发现，CXCR2可以促进ERK磷酸化。裸鼠腹腔种植模型显示，CXCR2可以促进卵巢癌细胞在体内的转移。该研究结果可以为开发靶向CXCR2的抗卵巢癌治疗药物提供依据。在相关小分子拮抗剂研究方面，我们发现了TMOC可以浓度依赖的抑制STAT3及其上游SRC激酶的磷酸化水平，从而抑制卵巢癌细胞的增殖，RY-2f可以通过抑制PI3K/AKT信号通路，在体内、体外显示出抗卵巢癌活性，增强顺铂的敏感性，具有进一步开发的前景和价值，为研究开发新型抗卵巢癌靶向药物打下了良好的实验室基础。