IL-6、IL-8上调卵巢癌细胞雄激素受体表达的作用分别依赖MAPK途径和Src活化  

IL-6-or IL-8-enhanced AR expression in ovarian carcinoma cells depends on MAPK pathway or Src activation

作　　者：王越[1] 杨洁[1] 高燕[2] 东莉洁[1] 姚智[1] 

机构地区：[1]天津医科大学免疫学教研室,天津300070 [2]天津市中心妇产科医院肿瘤科,天津300052

出　　处：《免疫学杂志》2008年第4期424-429,共6页Immunological Journal

基　　金：国家973重大基础研究前期研究专项项目(2003CCA04300);国家自然科学基金项目(30471962,30300070)

摘　　要：目的探讨IL-6、IL-8促进卵巢癌细胞增殖的分子机制。方法在以往工作的基础上,选择兼有IL-6、IL-8受体及雄激素受体(androgen receptor,AR)表达的卵巢癌细胞系SKOV-3和OVCAR-3作为研究模型,观察AR阻断剂氟他胺(flutamide,Flu)对IL-6、IL-8诱导的促卵巢癌细胞增殖作用的影响,在此基础上进一步探讨两种细胞因子对AR表达的调节作用及相关信号传导通路。结果①AR阻断剂Flu不能阻断反而增强IL-6、IL-8诱导的促卵巢癌细胞增殖效应。②在无雄激素的条件下,IL-6、IL-8不仅能增加AR表达而且还能活化AR基因启动子,后者可被Flu完全阻断。③IL-6诱导的AR水平增加可被p38 MAPK、MEK1/2及ErbB2 MAPK阻断剂阻断,而IL-8诱导的AR水平增加则可被Src阻断剂阻断。结论IL-6、IL-8很可能通过提高AR水平和AR活性从而增强卵巢癌细胞对雄激素的敏感性,由此通过产生的放大信号通路促进卵巢癌的生长和发展。IL-6、IL-8的上述活性分别依赖MAPK途径和Src活化。Objective To discover the molecular mechanism responsible for IL-6/IL-8-promoted ovarian carcinoma cell proliferation. Methods The effects of flutamide （Flu）, an androgen receptor （AR） antagonist, on IL-6/IL-8-induced cell proliferation of ovarian carcinoma was analyzed. Furthermore, the effects of IL-6 and IL-8 on AR expression and the related signal pathways were investigated. Gene expression profile analysis revealed that SKOV-3 and OVCAR-3 cells expressing both AR and IL-6/IL-8 receptors were suitable models for this study. Results In the absence of androgen, both IL-6 and IL-8 enhanced AR expression and AR promoter activation, which could be completely blocked by Flu. However, Flu failed to reduce IL-6-/IL-8-induced cell growth, p38 MAPK, MEK1/2, or ErbB2 MAPK iulaibitors could block IL-6-mediated enhancement of AR expression while Src inhibitor blocked IL-8 induced AR expression. Conclusion These data suggest that IL- 6 and IL-8 could elevate the sensitivity of ovarian carcinoma cells to androgen through increasing AR levels and activity, thus contribute to the growth and development of ovarian carcinoma by inducing an amplifying pathway. IL-6/IL-8-mediated increase of AR expression is dependent on MAPK pathway or the activation of Src.

关 键 词：IL-6 IL-8 卵巢癌 雄激素受体 MAPK SRE 

分 类 号：R737.31[医药卫生—肿瘤]