Ma Xue-Feng, Zhang Jie, Shuai Han-Lin, Guan Bao-Zhang, Luo Xin, Yan Rui-Ling
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China; Department of Gynecology and Obstetrics, Bao'an Maternal and Child Health Hospital, Shenzhen, China.
Department of Gynecology and Obstetrics, Bao'an Maternal and Child Health Hospital, Shenzhen, China.
Arch Biochem Biophys. 2015 May 1;573:52-8. doi: 10.1016/j.abb.2015.03.010. Epub 2015 Mar 19.
Cervical cancer is considered as the second most common female malignant disease. There is an urgent need to illustrate risk factors which can trigger the motility of cervical cancer cells. Our present study revealed that nanomolar concentration of bisphenol A (BPA) significantly promoted the in vitro migration and invasion of cervical cancer HeLa, SiHa, and C-33A cells. Further, BPA treatment increased the expression of metalloproteinase-9 (MMP-9) and fibronectin (FN) in both HeLa and SiHa cells, while did not obviously change the expression of MMP-2, vimentin (Vim) or N-Cadherin (N-Cad). BAY 11-7082, the inhibitor of NF-κB, significantly abolished BPA induced up regulation of FN and MMP-9 in cervical cancer cells. While the inhibitors of PKA (H89), ERK1/2 (PD 98059), EGFR (AG1478), or PI3K/Akt (LY294002) had no effect on the expression of either FN or MMP-9. BPA treatment rapidly increased the phosphorylation of both IκBα and p65, stimulated nuclear translocation, and up regulated the promoter activities of NF-κB. The BPA induced up regulation of MMP-9 and FN and activation of NF-κB were mediated by phosphorylation of IKKβ via PKC signals. Collectively, our study found for the first time that BPA stimulated the cervical cancer migration via IKK-β/NF-κB signals.
宫颈癌被认为是女性第二常见的恶性疾病。迫切需要阐明能够触发宫颈癌细胞运动的风险因素。我们目前的研究表明，纳摩尔浓度的双酚A（BPA）显著促进了宫颈癌HeLa、SiHa和C-33A细胞的体外迁移和侵袭。此外，BPA处理增加了HeLa和SiHa细胞中金属蛋白酶-9（MMP-9）和纤连蛋白（FN）的表达，而对MMP-2、波形蛋白（Vim）或N-钙黏蛋白（N-Cad）的表达没有明显影响。NF-κB抑制剂BAY 11-7082显著消除了BPA诱导的宫颈癌细胞中FN和MMP-9的上调。而蛋白激酶A（PKA）抑制剂（H89）、细胞外信号调节激酶1/2（ERK1/2）抑制剂（PD 98059）、表皮生长因子受体（EGFR）抑制剂（AG1478）或磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/Akt）抑制剂（LY294002）对FN或MMP-9的表达均无影响。BPA处理迅速增加了IκBα和p65的磷酸化，刺激了核转位，并上调了NF-κB的启动子活性。BPA诱导的MMP-9和FN上调以及NF-κB激活是通过蛋白激酶C（PKC）信号介导的IKKβ磷酸化实现的。总的来说，我们的研究首次发现BPA通过IKK-β/NF-κB信号刺激宫颈癌迁移。
