白介素-17在卵巢上皮癌侵袭转移中的功能及其分子机制研究

Interleukin-17(IL-17) signaling pathway has been verified participation in malignant process of many kinds tumors, however, its role in the occurrence and development of ovarian cancer is not clear. Our previous research has been found that IL-17 promoted ovarian cancer invasion, the possible reason is inducing the expression of metastasis-associated genes-1(MTA1); Corresponding, in clinical specimens, the expression of MTA1 is positive. It has been known that MTA1 directly regulates epithelial-to-mesenchymal transition (EMT) of tumor cells, based on the in vitro verification, we found that IL-17 can up-regulate MTA1 expression in ovarian cancer, activate Twist, Snail, Slug, promote Vimentin and N-cadherin expression, inhibit N-cadherin expression. According to these preliminary data, we hypothesize that the potential function and mechanisms of IL-17 in the development of ovarian cancer is: IL-17 up-regulates MTA1, initiates EMT, and induces invasion and metastasis of ovarian cancer. In order to test this hypothesis, we plan to increase ovarian cancer cell lines test, based on IL-17RA knockout mouse model of ovarian epithelial cancer, and collect the large clinical samples and prognostic data to further confirm the above research hypothesis, clarify its specific molecular signal pathway, analysis the relationship between molecules with invasion, metastasis and prognosis of ovarian cancer, to investigate the feasibility of IL-17 and MTA1 as novel therapeutic targets for ovarian cancer.

IL-17信号通路被证实参与多种肿瘤恶性演进，但其在卵巢癌发生发展中的作用尚不明确。前期研究我们发现IL-17刺激促进卵巢癌细胞侵袭，可能原因为增强肿瘤转移相关基因(MTA1)表达；与之对应卵巢癌临床标本中MTA1呈阳性表达。已知MTA1直接调控肿瘤细胞上皮间充质转化(EMT)，通过体外实验我们证实在卵巢癌细胞中IL-17上调MTA1，激活Twist、Snail、Slug进而促进Vimentin、N-cadherin表达，抑制E-cadherin表达。由此推测IL-17在卵巢癌进展中的潜在功能及机制为：IL-17上调MTA1，启动卵巢癌细胞EMT，诱导卵巢癌侵袭转移。本项目拟增加卵巢癌细胞株，基于IL-17RA基因敲除小鼠并借助大样本量临床标本及预后数据进一步证实以上研究假说，阐明其具体分子路径，分析相关分子与卵巢癌侵袭转移及预后的关系，研究IL-17及MTA1作为卵巢癌治疗靶点的可行性。

卵巢癌是妇科恶性肿瘤中死亡率最高的肿瘤，IL-17信号通路被证实参与多种肿瘤恶性演进，但其在卵巢癌发生发展中的作用尚不明确。本课题从细胞、动物、临床三个层次上全面深入研究IL-17在卵巢上皮癌侵袭转移中的功能及其分子机制，研究结果证实IL-17在卵巢癌进展中的潜在功能及机制为：IL-17刺激促进卵巢癌细胞侵袭，IL-17上调MTA1，启动卵巢癌细胞EMT，激活Twist、Snail、Slug进而促进Vimentin、N-cadherin表达，抑制E-cadherin表达，诱导卵巢癌侵袭转移。动物实验中IL-17阻滞剂Secukinumab以及MTA1阻滞剂Pterostilbene作用裸鼠后抑制MTA1表达，抑制Twist、Snail、Slug表达，进而抑制Vimentin、N-cadherin表达，促进E-cadherin表达，从而抑制卵巢上皮癌侵袭转移。在临床标本中，IL-17在卵巢上皮癌患者血清中表达显著高于非卵巢癌患者，MTA1及EMT相关因子在卵巢上皮癌组织中的表达显著增高。本研究探索了IL-17作为卵巢上皮癌新的治疗靶点可能性，为卵巢上皮癌靶向治疗新策略的制定和新药物开发提供了实验证据。