• Open Access

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

Authors

  • Xiaojun Chen,

    1. Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan;
    2. Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No. 419, Fang Xie Road 200011, Shanghai, China
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  • Akiko Horiuchi,

    Corresponding author
    1. Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan;
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  • Norihiko Kikuchi,

    1. Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan;
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  • Ryosuke Osada,

    1. Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan;
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  • Junko Yoshida,

    1. Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan;
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  • Tanri Shiozawa,

    1. Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan;
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  • Ikuo Konishi

    1. Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan;
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To whom correspondence should be addressed. E-mail: aki9hori@hsp.md.shinshu-u.ac.jp

Abstract

The hedgehog (Hh) signal pathway has recently been shown to be activated in human malignancies. However, little is known about its role in the development or patient prognosis of epithelial ovarian carcinoma. In the present study, we examined in vivo and in vitro the expression and functional role of Hh signal molecules in epithelial ovarian tumors and normal ovarian surface epithelial (OSE) cells. The expression of Shh, Dhh, Ptch, Smo and Gli1 proteins was not observed in normal OSE, but was increased stepwise in benign, borderline and malignant neoplasms. In addition, immunoreactivity for Shh, Dhh, Ptch, Smo and Gli1 was highly correlated with cell proliferation assessed by Ki-67. Blocking the Hh signal using either the Hh pathway inhibitor cyclopamine or Gli1 siRNA led to remarkably decreased cell proliferation in ovarian carcinoma cells. Treatment with cyclopamine induced not only G1 arrest but also apoptosis along with the downregulation of cyclin A and cyclin D1, and the upregulation of p21 and p27. Among the Hh signal molecules, Dhh expression was correlated with poor prognosis of ovarian carcinoma patients. These findings suggest that the Hh signal pathway plays an important role in ovarian tumorigenesis as well as in the activation of cell proliferation in ovarian carcinomas. Thus, the Hh signal pathway is a possible molecular target of new treatment strategies for ovarian carcinoma. (Cancer Sci 2007; 98: 68–76)

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