title: Activation of the signal transducer and activator of transcription 3 pathway up-regulates estrogen receptor-beta expression in lung adenocarcinoma cells.
abstract: 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.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Medical College, Tainan, Taiwan, Republic of China.
authors.forename: Hao-Chen
authors.initials: HC
authors.lastname: Wang
authors.forename: Hsuan-Heng
authors.initials: HH
authors.lastname: Yeh
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Huang
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Su
authors.forename: Helen H W
authors.initials: HH
authors.lastname: Chen
authors.forename: Wu-Wei
authors.initials: WW
authors.lastname: Lai
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
mesh_terms: D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology; D008175:Lung Neoplasms; D020935:MAP Kinase Signaling System; D020125:Mutation, Missense; D009376:Neoplasms, Hormone-Dependent; D010766:Phosphorylation; D011485:Protein Binding; D020871:RNA Stability; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D047629:Estrogen Receptor beta; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004815:Epidermal Growth Factor; D066246:ErbB Receptors