Activation of the Signal Transducer and Activator of Transcription 3 Pathway Up-Regulates Estrogen Receptor-beta Expression in Lung Adenocarcinoma Cells

作者：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^*

来源：Molecular Endocrinology, 2011, 25(7): 1145-1158.

DOI：10.1210/me.2010-0495

Estrogens contribute to the pathogenesis of female lung cancer and function mainly through estrogen receptor-beta (ER beta). However, the way in which ER beta 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 ER beta 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 ER beta mRNAand protein expression in lung cancer cells. The induction of ER beta 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 ER beta promoter. Besides the Janus kinase 2/Stat3 pathway, the MEK/Erk pathway contributes to ER beta 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 ER beta expression in lung cancer cells. Inhibiting Stat3 activity by pharmacological or genetic approaches reduced EGF- and L858R mutant EGFR-induced ER beta expression, indicating that Stat3 activation is required for EGFR signaling-mediated ER beta up-regulation. Silencing ER beta decreased cell proliferation in lung cancer cells that overexpress L858R mutant EGFR. In conclusion, we have identified that Stat3 activation is essential for ER beta 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. (Molecular Endocrinology 25: 1145-1158, 2011)

• 出版日期2011-7