"β-hCG-ERK1/2-MMP-2"信号通路在卵巢癌侵袭、转移中的作用研究

Epithelial ovarian cancer (EOC) carries a high mortality due to its properties of invasion and metastatic potential. It is considered that extracellular signal-regulated kinase (ERK1 / 2) signaling pathway and its downstream gene matrix metalloproteinases ( MMPs) play a key role in invasion and metastasis of EOC. Furthermore, researchers have demonstrated that β-hCG promotes invasion and metastasis in non-trophoblastic malignancies. In addition, we found previously that β-hCG could promote malignant transformation of immortalized human ovarian surface epithelial cells by enhancing proliferation and repressing apoptosis, leading to an increase of migration of those cells in vitro. However the mechanisms and involved signaling pathways for invasion and metastasis associated with β-hCG in ovarian cancer, are unknown. We intend to investigate the role of β-hCG in inducing expression of ERK1 / 2 and MMP-2 and promoting the ability of invasion and migration in human ovarian cancer SKOV3 cells and nude mice xenograft as well. In addition, we will investigate the expression levels of β-hCG, ERK1 / 2 and MMP-2 in primary and metastatic EOC tissue specimens . We expect to shed light on the role of β-hCG in inducing invasion and metastasis by means of a probable "β-hCG-ERK1/2-MMP-2" signaling pathway and provide a novel approach for personalized targeted therapy in patients suffering from epithelial ovarian cancer.

侵袭、转移是卵巢癌死亡率高的主要原因。细胞外信号调节激酶 (ERK1/2)信号通路及其下游基因基质金属蛋白酶（MMPs）的协同作用是肿瘤侵袭、迁移的关键环节。研究表明，β-hCG促进非妊娠滋养细胞肿瘤侵袭、转移。前期研究证实β-hCG通过促进增殖、阻遏凋亡等途径，促使永生化人卵巢表面细胞恶性转化，增加其体外迁移力。但β-hCG是否促进卵巢癌侵袭、转移？通过何种通路发挥作用不详。本课题拟研究β-hCG对SKOV3细胞ERK1/2、MMP2表达及体外侵袭、迁移能力的作用；观察β-hCG对裸鼠原位移植瘤ERK1/2、MMP2表达及体内侵袭、转移的作用；分析人卵巢癌原发及转移肿瘤组织中β-hCG与ERK1/2、MMP-2表达的相关性。阐明"β-hCG-ERK1/2-MMP-2"信号通路在卵巢癌侵袭、转移中的作用，初步探讨β-hCG促进卵巢癌侵袭、转移的分子机制，为探寻个体化的靶向治疗提供新途径。

上皮性卵巢癌（EOC）的病死率高居妇科恶性肿瘤之首，极易发生侵袭转移是导致其预后差的主要原因，但其机制不详。课题组预实验证实：β-hCG在EOC转移瘤中异常高表达，推测其可能与EOC侵袭、转移相关。课题建立β-hCG上、下调的 EOC细胞模型和裸鼠卵巢原位移植瘤动物模型，在此基础上证实上调β-hCG显著促进EOC迁移、侵袭，促进EOC细胞伪足形成、线粒体聚集及细胞骨架重塑，下调β-hCG诱发的生物学效应与上调相反；β-hCG与p-ERK1/2及MMP-2的表达密切相关，下调p-ERK1/2可显著逆转上调β-hCG促进EOC迁移、转移的效应。本研究的结果总结，β-hCG具有显著调控EOC迁移、侵袭的作用，“β-hCG-ERK1/2-MMP-2”信号通路是诱导EOC迁移、侵袭的重要机制之一 。本研究结果在理论上加深了我们对EOC侵袭、转移调控机制的理解；同时为临床前(pre-clinical)通过调控β-hCG进而诱导体内p-ERK1/2表达水平改变的分子靶向治疗提供坚实的实验依据。