Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells
Department of Surgery
Adult; Antigens, CD; Cell Division; Cell Line; Cytokine Receptor gp130; DNA-Binding Proteins; Dose-Response Relationship, Drug; Epithelial Cells; Female; Genes, Dominant; Gonadotropins; Humans; Immunoblotting; Interleukin-6; Membrane Glycoproteins; Middle Aged; Ovarian Neoplasms; Ovary; RNA, Messenger; Receptors, Interleukin-6; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Signal Transduction; Trans-Activators; Transfection; Tumor Cells, Cultured
Life Sciences | Medicine and Health Sciences
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 alpha chain (IL-6Ralpha), 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), 17beta-estradiol, or estrone but increased only in OVCA cells treated with testosterone and 5alpha-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-6Ralpha 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
DOI of Published Version
J Natl Cancer Inst. 2002 Apr 17;94(8):617-29.
Journal of the National Cancer Institute
Syed, Viqar; Ulinski, Gregory; Mok, Samuel C.; and Ho, Shuk-Mei, "Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells" (2002). Open Access Articles. 1160.