© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 8, 617-629,
April 17, 2002
© 2002 Oxford University Press
ARTICLE |
Reproductive Hormone-Induced, STAT3-Mediated Interleukin 6 Action in Normal and Malignant Human Ovarian Surface Epithelial Cells
Affiliations of authors: V. Syed (Department of Surgery), S.-M. Ho (Department of Surgery and Cell Biology), University of Massachusetts Medical School, Worcester; G. Ulinski, Worcester Polytechnic Institute, Worcester; S. C. Mok, Laboratory of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston.
Correspondence to: Shuk-Mei Ho, Ph.D., Department of Surgery, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655 (e-mail: shuk-mei.ho{at}umassmed.edu).
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 
chain (IL-6R), 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), 17
-estradiol, or estrone but increased only in OVCA cells treated with testosterone and 5-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-6R 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<.001; OVCA 432 cells, P<.006), whereas wild-type STAT3 enhanced HOSE cell proliferation (wild-type STAT3 at 0.5 µg/mL in HOSE 306 cells, P<.002; STAT3 at 1.0 µg/mL in HOSE 306 or both concentrations of wild-type STAT3 in HOSE 642 cells, P<.001). Conclusions: The IL-6/STAT3 signaling pathway may mediate FSH-, LH-, and estrogen-stimulated HOSE cell proliferation. Increased IL-6R expression and constitutive STAT3 activation may be associated with ovarian cancer.
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