Hua Keqin, Feng Weiwei, Cao Qi, Zhou Xianrong, Lu Xin, Feng Youji
Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, PR China.
Int J Oncol. 2008 Nov;33(5):959-67.
Estrogen and progestin are involved in ovarian carcinogenesis. Change in nm23-H1 expression and the PIK3/AKT pathway are involved in carcinogenesis, development, invasion and metastasis of ovarian cancers. Therefore, it is critical to understand the signaling pathways that regulate hormone-induced cell migration and invasion in ovarian cancer. We investigated nm23-H1, AKT and pAKT expression by using immunohistochemical staining in ovarian clear cell adenocarcinoma, ovarian benign, borderline and malignant serous tumors and analyzed their relationship with prognostic factors. Using ES-2 and SKOV-3 ovarian cancer cell lines, we studied the modulation of estrogen and progestin on cell migration and invasion as well as their effect on AKT, pAKT and nm23-H1 expression. Furthermore, the signaling pathways were examined using pharmacological inhibitors (LY294002 and PD98059) or AKT siRNA combined with estrogen or progestin in the two cell lines. Weak nm23-H1 and high AKT and pAKT expression was observed in ovarian serous adeno-carcinoma and ovarian clear cell adenocarcinoma. Our data demonstrated that the expression of nm23-H1 was negatively correlated with tumor stage and grade and lymph node metastasis, whereas the expression of AKT/pAKT was positively correlated with these clinic factors. Estrogen up-regulated pAKT expression and reduced nm23-H1 expression, which ultimately resulted in increased cell migration and invasion. In contrast, progestin reduced pAKT expression and increased nm23-H1 expression, which inhibited cell migration. PIK3 kinase inhibitor LY294002 antagonized the effect of estrogen. On the other hand, it reinforced the effect of progestin. Our data suggest that AKT and pAKT are unfavorable prognostic factors for ovarian serous adenocarcinoma and clear cell carcinomas whereas nm23-H1 expression predicates favorable patient prognosis. Estrogen down-regulates nm23-H1 expression and promotes cell migration and invasion by activating the PIK3/AKT pathway. Progestin has an opposing effect.
雌激素和孕激素参与卵巢癌的发生。nm23-H1表达的变化以及PIK3/AKT信号通路参与卵巢癌的发生、发展、侵袭和转移。因此，了解调节激素诱导的卵巢癌细胞迁移和侵袭的信号通路至关重要。我们通过免疫组织化学染色研究了nm23-H1、AKT和pAKT在卵巢透明细胞腺癌、卵巢良性、交界性和恶性浆液性肿瘤中的表达，并分析了它们与预后因素的关系。利用ES-2和SKOV-3卵巢癌细胞系，我们研究了雌激素和孕激素对细胞迁移和侵袭的调节作用以及它们对AKT、pAKT和nm23-H1表达的影响。此外，在这两种细胞系中使用药理学抑制剂（LY294002和PD98059）或AKT siRNA联合雌激素或孕激素来检测信号通路。在卵巢浆液性腺癌和卵巢透明细胞腺癌中观察到nm23-H1表达较弱，AKT和pAKT表达较高。我们的数据表明，nm23-H1的表达与肿瘤分期、分级和淋巴结转移呈负相关，而AKT/pAKT的表达与这些临床因素呈正相关。雌激素上调pAKT表达并降低nm23-H1表达，最终导致细胞迁移和侵袭增加。相反，孕激素降低pAKT表达并增加nm23-H1表达，从而抑制细胞迁移。PI3激酶抑制剂LY294002拮抗雌激素的作用。另一方面，它增强了孕激素的作用。我们的数据表明，AKT和pAKT是卵巢浆液性腺癌和透明细胞癌的不良预后因素，而nm23-H1表达预示患者预后良好。雌激素通过激活PIK3/AKT信号通路下调nm23-H1表达并促进细胞迁移和侵袭。孕激素则具有相反的作用。
