雌激素与IL-6、IL-8在卵巢癌细胞中的调节作用

Regulation of estrogen, interleukin-6 and interleukin-8 in ovarian cancer cells

目的探讨雌激素与IL-6、IL-8在卵巢癌细胞中的交互调节作用及作用机制。方法选择兼有雌激素受体（estrogen receptor，ER）及IL-6、IL-8受体表达的卵巢癌细胞系CAOV-3和OVCAR-3作为研究模型，分别探讨17β-雌二醇（estradiol，E2）对IL-6、IL-8及其受体表达的作用以及IL-6、IL-8对ER表达及ER转录活性的作用。结果一方面E2不仅可经NF—κB途径促进卵巢癌细胞IL-6、IL-8分泌，而且还对二者受体的表达具有一定的调节作用。E2诱导的促IL-6、IL-8分泌作用可被其受体阻断剂他莫昔芬（tamoxifen，Txf）完全阻断。另一方面在无雌激素的条件下，IL-6、IL-8能上调卵巢癌细胞ERα表达及下调ERβ表达，且还能分别通过丝裂原活化蛋白激酶（MAPK）信号通路和Src活化增强卵巢癌细胞ER的转录活性，该作用可被Txf完全封闭。结论雌激素与IL-6、IL-8两种细胞因子在卵巢癌细胞中交互调节，由此通过产生的放大信号通路促进卵巢癌的生长和发展。

Objective To discover the reciprocal regulation and its molecular mechanism of estrogen, IL-6 and IL-8 in ovarian cancer cells. Methods Based on our previous studies, the effect of 17β- estradiol （ E2 ） on the expression levels of IL-6, IL-8 and their respective receptors was investigated. Meanwhile, the effect of IL-6/IL-8 on estrogen receptor （ER） expression and estrogen-dependent transcriptional activation was analyzed. Gene expression profile analysis revealed that CAOV-3 and OVCAR-3 cells, which express ER, IL-6 and IL-8 receptors, were suitable models for this study. Results We found that E2 not only enhanced IL-6/IL-8 secretion via NF-κB signaling pathway, but also modulated IL-6 and IL-8 receptors expression. Tamoxifen （Txf）, an ER antagonist, completely abolished E2-stimulated IL-6/IL-8 expression. On the other hand, in the absence of estrogen, both cytokines increased ERa expression, decreased ERβ expression, and activated estrogen-dependent transcriptional activation, which was completely blocked by Txf. Pretreatment of OVCAR-3 with p38 MAPK, MEK1/2 or ErbB2 MAPK inhibitors, respectively, IL-6-mediated ER activation was blocked, while IL-8-induced ER activation was blocked by Src inhibitor. Conclusion These data suggest that estrogen, IL-6 and IL-8 may form a mutual amplifying signaling which contributes to the growth and development of ovarian carcinoma.