Wang Hao-Chen, Yeh Hsuan-Heng, Huang Wei-Lun, Lin Chien-Chung, Su Wen-Pin, Chen Helen H W, Lai Wu-Wei, Su Wu-Chou
Institute of Basic Medical Sciences, National Cheng Kung University, Medical College, Tainan, Taiwan, Republic of China.
Mol Endocrinol. 2011 Jul;25(7):1145-58. doi: 10.1210/me.2010-0495. Epub 2011 May 5.
Estrogens contribute to the pathogenesis of female lung cancer and function mainly through estrogen receptor-β (ERβ). However, the way in which ERβ expression is regulated in lung cancer cells remains to be explored. We have found that signal transducer and activator of transcription 3 (Stat3) activation up-regulates ERβ expression in PC14PE6/AS2 lung cancer cells in a preliminary Affymetrix oligonucleotide array study, and we sought to confirm the findings. In this study, we show that IL-6 induced ERβ mRNA and protein expression in lung cancer cells. The induction of ERβ in response to IL-6 was abolished by Janus kinase 2 inhibitor-AG490, dominant-negative mutant of Stat3, and Stat3-targeting short interfering RNA. The luciferase reporter assay and chromatin immunoprecipitation assay confirmed that IL-6-activated Stat3 binds to the ERβ promoter. Besides the Janus kinase 2/Stat3 pathway, the MEK/Erk pathway contributes to ERβ up-regulation induced by IL-6; however, the phosphoinositide 3'-kinase/Akt pathway does not. We also found that epidermal growth factor (EGF) stimulation or L858R mutation in EGF receptor (EGFR) induced Stat3 activation as well as ERβ expression in lung cancer cells. Inhibiting Stat3 activity by pharmacological or genetic approaches reduced EGF- and L858R mutant EGFR-induced ERβ expression, indicating that Stat3 activation is required for EGFR signaling-mediated ERβ up-regulation. Silencing ERβ decreased cell proliferation in lung cancer cells that overexpress L858R mutant EGFR. In conclusion, we have identified that Stat3 activation is essential for ERβ induction by IL-6, EGF, and the presence of EGFR mutation. The findings shed light on new therapeutic targets for female lung cancer, especially for those with EGFR mutations.
雌激素参与女性肺癌的发病机制，主要通过雌激素受体-β（ERβ）发挥作用。然而，肺癌细胞中ERβ表达的调控方式仍有待探索。在一项初步的Affymetrix寡核苷酸芯片研究中，我们发现信号转导及转录激活因子3（Stat3）的激活上调了PC14PE6/AS2肺癌细胞中ERβ的表达，我们试图证实这一发现。在本研究中，我们表明白细胞介素-6（IL-6）可诱导肺癌细胞中ERβ的mRNA和蛋白表达。对IL-6作出反应而诱导的ERβ表达被Janus激酶2抑制剂AG490、Stat3的显性负性突变体以及靶向Stat3的小干扰RNA所消除。荧光素酶报告基因检测和染色质免疫沉淀检测证实，IL-6激活的Stat3与ERβ启动子结合。除了Janus激酶2/Stat3途径外，MEK/Erk途径也参与IL-6诱导的ERβ上调；然而，磷酸肌醇3'-激酶/Akt途径则不然。我们还发现，表皮生长因子（EGF）刺激或EGF受体（EGFR）中的L858R突变可诱导肺癌细胞中Stat3激活以及ERβ表达。通过药理学或遗传学方法抑制Stat3活性可降低EGF和L858R突变型EGFR诱导的ERβ表达，表明Stat3激活是EGFR信号介导的ERβ上调所必需的。沉默ERβ可降低过表达L858R突变型EGFR的肺癌细胞的增殖。总之，我们已经确定Stat3激活对于IL-6、EGF诱导的ERβ表达以及EGFR突变的存在至关重要。这些发现为女性肺癌，尤其是那些具有EGFR突变的肺癌，揭示了新的治疗靶点。
