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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-08-0117v1 16/1/113    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kashima, H. Articles by Konishi, I. Search for Related Content PubMed PubMed Citation Articles by Kashima, H. Articles by Konishi, I.

H Kashima, OB/GYN, Shinshu University School of Medicine, Matsumoto, Japan
T Shiozawa, Obstetrics & Gynecology, Shinshu University, Matsumoto, 390-8621, Japan
T Miyamoto, OB/GYN, Shinshu University School of Medicine, Matsumoto, Japan
A Suzuki, OB/GYN, Shinshu University School of Medicine, Matsumoto, Japan
J Uchikawa, OB/GYN, Shinshu University School of Medicine, Matsumoto, Japan
M Kurai, OB/GYN, Shinshu University School of Medicine, Matsumoto, Japan
I Konishi, OB/GYN, Shinshu University School of Medicine, Matsumoto, Japan

Correspondence: Tanri Shiozawa, Email: tanri{at}hsp.md.shinshu-u.ac.jp

Abstract

To examine estrogen-induced growth mechanisms of endometrial carcinoma, we investigated the estrogen-induced activation of the mitogen-activated protein kinase (MAPK) pathway and cell cycle regulators. Estradiol (E2) treatment at concentrations of 10-8M and 10-6M to estrogen receptor (ER)-positive endometrial carcinoma Ishikawa cells for 24 hours resulted in increased cell proliferation by 20% and 28%, respectively. The E2-induced proliferation was associated with activation of extracellular signal-regulated kinase (ERK)1/2 and up-regulation of cyclin D1 and E, which were suppressed by the addition of a MEK inhibitor (U0126) or an ER antagonist (ICI182,780). Then, our screening for estrogen-inducible growth factors identified that insulin-like growth factor (IGF)-1 was up-regulated remarkably by E2. Immunoprecipitation using conditioned medium of Ishikawa cells after E2 treatment confirmed the E2-induced secretion of IGF-1 protein. Treatment with recombinant IGF-1 stimulated cell proliferation in a dose-dependent fashion, in association with ERK1/2 phosphorylation and up-regulation of cyclin D1 and E. These IGF-1-induced responses were suppressed by treatment with MEK inhibitor, or anti-IGF-1 receptor antibody. Immunohistochemical staining confirmed the expression of activated ERK1/2 in normal proliferative phase endometria and endometrial carcinomas, indicating the involvement of this pathway in actively proliferating endometrial tissues in vivo. These findings suggest that E2-induced proliferation of endometrial carcinoma cells is mediated by the ERK1/2 pathway via autocrine stimulation of IGF-1.