Zhang Jieqing, Song Honglin, Lu Yanqiong, Chen Haiyan, Jiang Si, Li Li
Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
Oncol Rep. 2016 Aug;36(2):705-14. doi: 10.3892/or.2016.4888. Epub 2016 Jun 21.
Endometrial carcinogenesis may be related to the long-term effects of estradiol with no antagonism. However, how estradiol regulates cell proliferation is unknown. In the present study, through investigating the molecular events involved in estradiol induced angiogenics factors VEGF and bFGF, we found that estradiol induced endometrial cancer cell division, proliferation, migratory and invasive capacity in vitro and upregulated mRNA expression and protein synthesis of VEGF and bFGF. The estradiol-dependent induction of the expression of VEGF and bFGF was blocked by ER inhibitor, AKT inhibitor and NF-κB inhibitor (PDTC) in estrogen receptor positive Ishikawa cells and blocked by AKT inhibitor, NF-κB inhibitor (PDTC) in estrogen receptor negative HEC-1A cells. Moreover, estradiol activation of AKT was also blocked by AKT antagonist. NF-κB activation was restricted by estradiol concentration and time. Estradiol leading to VEGF and bFGF induction was also confirmed by the development of xenograft tumors in vivo. Taken together, our data suggest that estradiol induces the production of angiogenic factors via a mechanism involving AKT-mediated NF-κB activation partly in non-genomic manner without the estrogen receptor.
子宫内膜癌发生可能与长期无拮抗作用的雌二醇效应有关。然而，雌二醇如何调节细胞增殖尚不清楚。在本研究中，通过研究雌二醇诱导血管生成因子VEGF和bFGF所涉及的分子事件，我们发现雌二醇在体外诱导子宫内膜癌细胞分裂、增殖、迁移和侵袭能力，并上调VEGF和bFGF的mRNA表达及蛋白质合成。在雌激素受体阳性的Ishikawa细胞中，ER抑制剂、AKT抑制剂和NF-κB抑制剂（PDTC）可阻断雌二醇依赖性的VEGF和bFGF表达诱导；在雌激素受体阴性的HEC-1A细胞中，AKT抑制剂、NF-κB抑制剂（PDTC）可阻断该诱导。此外，AKT拮抗剂也可阻断雌二醇对AKT的激活。NF-κB的激活受雌二醇浓度和时间的限制。体内异种移植瘤的形成也证实了雌二醇可导致VEGF和bFGF的诱导。综上所述，我们的数据表明，雌二醇通过一种部分涉及AKT介导的NF-κB激活的机制，以非基因组方式在无雌激素受体的情况下诱导血管生成因子的产生。
