Expression of estrogen receptor alpha increases leptin-induced STAT3 activity in breast cancer cells
Expression of estrogen receptor alpha increases leptin-induced STAT3 activity in breast cancer cells
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DOI：
10.1002/ijc.25010
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发表时间：
2010-07-01
影响因子：
6.4
通讯作者：
Wessler, Silja
中科院分区：
文献类型：
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作者：
Binai, Nadine A.;Damert, Annette;Wessler, Silja
脂肪与患乳腺癌、子宫内膜肿瘤或前列腺癌等恶性疾病的风险增加相关，但其分子基础尚不清楚。潜在的机制包括增加脂肪细胞因子（例如瘦素）和类固醇激素的生物利用度。在这里，我们研究了 ER α（雌激素受体 α）与瘦素诱导的信号转导子和转录激活子 3 (STAT3) 激活（重要癌基因的反式激活子）之间的串扰。当瘦素与其受体 Ob-RL（肥胖受体）结合后，STAT3 酪氨酸磷酸化和反式激活活性通过同时表达 ERa 得到增强。使用小干扰 RNA 下调 ERa 可消除瘦素诱导的 STAT3 磷酸化。有趣的是，瘦素介导的 STAT3 激活不受 ERa 配体雌二醇 (E2) 或雌激素拮抗剂 10182,780 和他莫昔芬共刺激的影响，这意味着瘦素介导的 STAT3 活性的增强与 ERa 配体无关。我们还检测到 ERa 与 STAT3 和 JAK2（Janus 激酶 2）结合，导致 STAT3 上游的 JAK2 活性增强，以响应瘦素，这可能导致 ER α 依赖性细胞活力增加。总而言之，我们的结果表明瘦素诱导的 STAT3 激活是 ER α 依赖性恶性疾病发展的关键事件。
Adipositas correlates with an enhanced risk of developing malignant diseases such as breast cancer, endometrial tumor or prostate carcinoma, but the molecular basis for this is not well understood. Potential mechanisms include increased bioavailability of adipocytokines (e.g. leptin) and steroid hormones. Here, we investigated cross-talk between ER alpha (estrogen receptor alpha) and leptin-induced activation of signal transducer and activator of transcription 3 (STAT3), a transactivator of important oncogenes. Upon leptin binding to its receptor Ob-RL (obesity receptor), STAT3 tyrosine phosphorylation and transactivation activity were enhanced by simultaneously expressing ERa. Downregulation of ERa using small interfering RNA abolished leptin-induced STAT3 phosphorylation. Interestingly, leptin-mediated STAT3 activation was unaffected by co-stimulation with the ERa ligands estradiol (E2) or estrogen antagonists 10182,780 and tamoxifen, implying that enhancement of leptin-mediated STAT3 activity is independent of ERa ligands. We also detected ERa binding to STAT3 and JAK2 (Janus kinase 2), resulting in enhanced JAK2 activity upstream of STAT3 in response to leptin that might lead to an increased ER alpha-dependent cell viability. Altogether, our results indicate that leptin-induced STAT3 activation acts as a key event in ER alpha-dependent development of malignant diseases.