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Annals of Oncology Advance Access originally published online on August 9, 2008
Annals of Oncology 2009 20(1):63-70; doi:10.1093/annonc/mdn556
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

gynecologic tumours

Hepatocyte growth factor activator inhibitor-2 (HAI-2) is a favorable prognosis marker and inhibits cell growth through the apoptotic pathway in cervical cancer

K. Nakamura1,*, F. Abarzua2, A. Hongo1, J. Kodama1, Y. Nasu2, H. Kumon2 and Y. Hiramatsu1

1 Department of Obstetrics and Gynecology
2 Department of Urology, Okayama University Graduate School of Medical, Dentistry and Pharmaceutical Sciences, Okayama, Japan

* Correspondence to: Dr K. Nakamura, Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Tel: +81-86-235-7320; Fax: +81-86-235-9570; E-mail: k-nakamu{at}cc.okayama-u.ac.jp

Background: In light of the poor prognosis for cervical cancer, research continues into the development of innovative and efficacious treatment modalities for this disease. We investigated the role of hepatocyte growth factor activator inhibitor-2 (HAI-2) and evaluated its clinical importance in cervical cancer.

Patients and methods: HAI-2 expression was examined in cervical cancer specimens (n = 52) by immunohistochemistry. We further attempted to investigate the biological functions and inhibitory effects of HAI-2 using human papillomavirus (HPV) 16 type SiHa and HPV 18 type HeLa cervical cancer cell lines.

Results: There were significant correlations between HAI-2 expression and stage (P = 0.017), lymph node metastasis (P = 0.005) and ovarian metastasis (P = 0.038). Low HAI-2 expression was a significant predictor for a poor prognosis compared with high HAI-2 expression (disease-free survival rate, P = 0.016; overall survival rate, P = 0.021). After transient transfection into the SiHa and HeLa cell lines, HAI-2 showed potential inhibitory effects mediated by reductions in hepsin and matriptase expression, which led to apoptosis by increasing the level of Bak and reducing the level of Bcl-2.

Conclusions: The present findings indicate that low HAI-2 expression in cervical cancer may be associated with a poor prognosis. We propose that HAI-2 may represent a therapeutic target for the treatment of cervical cancer.

Key words: apoptosis, cervical cancer, favorable prognosis marker, HAI-2

Received for publication April 11, 2008. Revision received July 10, 2008. Accepted for publication July 15, 2008.


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