Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells.
Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells.
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生殖激素诱导的、STAT3 介导的白细胞介素 6 在正常和恶性人卵巢表面上皮细胞中的作用。
DOI：
10.1093/jnci/94.8.617
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Ho,Shuk-Mei
中科院分区：
文献类型：
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作者：
Syed,Viqar;Ulinski,Gregory;Mok,SamuelC;Ho,Shuk-Mei
背景：生殖激素与上皮性卵巢癌的风险相关。为了确定这些激素对白细胞介素6（IL-6）/STAT 3活化的影响，（信号转导子和转录激活子-3）信号传导可能参与卵巢癌，我们研究了永生化人卵巢表面上皮（HOSE）和卵巢癌（OVCA）细胞系中STAT 3、IL-6及其受体的状态。方法：将两种永生化HOSE细胞系和两种OVCA细胞系与促性腺激素、性类固醇激素和/或IL-6单独或与特异性抑制剂或IL-6中和抗体一起培养。测定所有细胞中IL-6、IL-6受体α链（IL-6 R α）以及磷酸化和非磷酸化STAT 3信使RNA（mRNA）和蛋白质的表达。评估细胞增殖和软琼脂集落形成。在用显性负性STAT 3（Dn-STAT 3）、野生型STAT 3或空对照载体转染的OVCA细胞中研究STAT 3活性。结果：IL-6 mRNA和蛋白水平在卵泡刺激素（FSH）、促黄体生成素（LH）、17β-雌二醇（E2）和雌酮（E3）处理的卵巢癌细胞中均升高，但仅在睾酮和5α-二氢睾酮处理的卵巢癌细胞中升高。对于所有细胞系，IL-6抗体部分抑制了IL-6刺激的细胞增殖，但完全抑制了IL-6增强的细胞增殖。IL-6诱导HOSE细胞中STAT 3磷酸化和活化; OVCA细胞中STAT 3组成性活化。OVCA细胞中IL-6 R α和STAT 3转录因子的表达水平高于HOSE细胞。转染后，Dn-STAT 3抑制内源性STAT 3，并抑制所有形式的IL-6刺激的OVCA细胞增殖（OVCA 429细胞，P<.001; OVCA 432细胞，P<.006），而野生型STAT 3增强HOSE细胞增殖（HOSE 306细胞中0.5 μg/mL的野生型STAT 3，P<.002; HOSE 306中1.0 μg/mL的STAT 3或HOSE 642细胞中两种浓度的野生型STAT 3，P<.001）。IL-6/STAT 3信号通路可介导FSH、LH和雌激素刺激的HOSE细胞增殖。IL-6 R α表达增加和组成性STAT 3激活可能与卵巢癌相关。
Background:Reproductive hormones are associated with risk for epithelial ovarian cancer. To determine the effect of such hormones on the activation of interleukin 6 (IL-6)/STAT3 (signal transducer and activator of transcription-3) signaling, which may be involved in ovarian cancer, we investigated the status of STAT3, IL-6, and its receptor in immortalized human ovarian surface epithelial (HOSE) and ovarian cancer (OVCA) cell lines.Methods:Two immortalized HOSE cell lines and two OVCA cell lines were cultured with gonadotropins, sex steroid hormones, and/or IL-6, alone or with specific inhibitors or IL-6-neutralizing antibodies. Expression of IL-6, the IL-6 receptor α chain (IL-6Rα), and phosphorylated and unphosphorylated STAT3 messenger RNAs (mRNAs) and proteins in all cells was determined. Cell proliferation and soft-agar colony formation were assessed. STAT3 activity was investigated in OVCA cells transfected with a dominant negative STAT3 (Dn-STAT3), wild-type STAT3, or an empty control vector. All statistical tests were two-sided.Results:Levels of IL-6 mRNA and protein increased in all cells treated with follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17β-estradiol, or estrone but increased only in OVCA cells treated with testosterone and 5α-dihydrotestosterone. For all lines, IL-6 antibodies partially inhibited hormone-stimulated cell proliferation but completely inhibited IL-6-enhanced cell proliferation. IL-6 induced STAT3 phosphorylation and activation in HOSE cells; STAT3 was constitutively activated in OVCA cells. Higher levels of IL-6Rα and STAT3 transcription factors were observed in OVCA cells than in HOSE cells. After transfection, Dn-STAT3 suppressed endogenous STAT3 and inhibited all forms of IL-6-stimulated OVCA cell proliferation (OVCA 429 cells,P<.001; OVCA 432 cells,P<.006), whereas wild-type STAT3 enhanced HOSE cell proliferation (wild-type STAT3 at 0.5 μg/mL in HOSE 306 cells,P<.002; STAT3 at 1.0 μg/mL in HOSE 306 or both concentrations of wild-type STAT3 in HOSE 642 cells,P<.001).Conclusions:The IL-6/STAT3 signaling pathway may mediate FSH-, LH-, and estrogen-stimulated HOSE cell proliferation. Increased IL-6Rα expression and constitutive STAT3 activation may be associated with ovarian cancer.