IL-6经MEK/ERK途径促进ERα-Ser118磷酸化影响卵巢癌细胞他莫昔芬耐药  

IL-6 strengthens Tamoxifen resistance of ovarian cancer cells by promoting ERα-Ser118 phosphorylation though the MEK/ERK pathway

作　　者：韦依依 孙旸[2] 黄素辉[3] 郭小芹[3] 牛秀珑[2] 王越[3] 杨静[3] 付正英[2] 

机构地区：[1]天津中医药大学,300193 [2]武警后勤学院附属医院妇产科,天津300162 [3]武警后勤学院病原生物与免疫学教研室,天津300309

出　　处：《免疫学杂志》2017年第4期294-300,共7页Immunological Journal

基　　金：国家自然科学基金(81572852,81273520,81502256);武警后勤学院科学技术研究项目(WHB201505,WHB201404,2015ZXKF05,WHB201610)

摘　　要：目的研究IL-6信号通路对ERα的Ser118位点磷酸化影响、对ERα转录活性的影响及IL-6诱导卵巢癌TAM耐药的机制。方法脂质体转染法获得内源性过表达IL-6的人卵巢癌A2780细胞株和内源性抑制IL-6表达的人卵巢癌CAOV3细胞株,Western blot法检测内源性和外源性IL-6对ERK和ERα的Ser118位点磷酸化影响,MTT法检测IL-6的MEK/ERK信号通路对A2780细胞TAM耐药性的影响,荧光素酶活性检测IL-6的MEK/ERK信号通路对ERα转录活性的影响。结果过表达IL-6能上调A2780细胞中ERα-Ser118的磷酸化水平,而抑制IL-6表达下调CAOV3细胞中ERα-Ser118的磷酸化水平;外源性IL-6上调A2780细胞中ERK的磷酸化水平,而MEK1/2特异性抑制剂PD98059则可以逆转IL-6介导的ERK及ERα-Ser118的磷酸化;PD98059可明显降低IL-6导致的A2890细胞对TAM的耐药性;IL-6明显促进ERα转录活性,而PD98059可逆转这一作用。结论 IL-6经MEK/ERK通路磷酸化ERα的Ser118位点促进ERα转录活性而激活ER途径,诱导OVCA细胞对TAM的耐药性。This study was designed to study the effect of IL-6 signal pathway on the phosphorylation of ERα at Ser118 site and the transcriptional activity of ERα, and to explore the mechanism of IL-6-induced Tamoxifen（TAM）resistance in ovarian cancer. Human ovarian cancer A2780 cell line with endogenous overexpression of IL-6 and human ovarian cancer CAOV3 cell line with endogenous inhibition of IL-6 expression were obtained by lipofection.phosphorylation of ERK and Ser118 sites in ERα were detected by Western blot assay; the effect of MEK/ERK signaling pathway of IL-6 on TAM resistance in A2780 cells was detected by MTT assay; the effect of MEK/ERK signaling pathway of IL-6 on the transcriptionalactivity of ERα was detected by Luciferase activityassay. Data showed that overexpression of IL-6 upregulated the phosphorylation of ERα-Ser118 in A2780 cells andthe inhibition of IL-6 expression downregulated ERα-Ser118 phosphorylation in CAOV3 cells; IL-6 upregulatedthe phosphorylation of ERK in A2780 cells, and MEK1/2 specific inhibitor PD98059 could reverse theIL-6-mediated ERK and ERα-Ser118 phosphorylation. PD98059 could significantly reduce IL-6-inducedresistance to TAM in A2890 cells; IL-6 significantly promoted ERα transcription activity, and PD98059 can reversethis effect. In conclusion, IL-6 phosphorylates Ser118 site of ERα by activating MEK/ERK signaling pathway,promotes ERα transcriptional activity, then activates ER pathway and induces resistance of TAM to OVCA cells.

关 键 词：IL-6 卵巢癌 他莫昔芬耐药 ERΑ ERK 

分 类 号：R737.31[医药卫生—肿瘤]