This Article Full Text Full Text (PDF) Supplementary Material 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 Chen, Y.-J. Articles by Leu, T.-H. Search for Related Content PubMed PubMed Citation Articles by Chen, Y.-J. Articles by Leu, T.-H.

Research Articles: Therapeutics, Targets, and Development

Eps8 decreases chemosensitivity and affects survival of cervical cancer patients

¹ Institute of Basic Medical Sciences, Department of Pharmacology, College of Medicine, and Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan; and ² Institute of Molecular Systems Biomedicine and ³ Institute of Medical Science, China Medical University, Taichung, Taiwan

Requests for reprints: Ming-Chei Maa, Institute of Medical Science, China Medical University, Taichung 40402, Taiwan, People's Republic of China. Phone: 886-4-2205-3366, ext. 2202; Fax: 886-4-2205-3764. E-mail: mcmaa{at}mail.cmu.edu.tw or Tzeng-Horng Leu, Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. Phone: 886-6-235-3535, ext. 5468; Fax: 886-6-274-9296. E-mail: tzengleu@mail.ncku.edu.tw

Abstract

The oncoprotein Eps8 facilitates proliferation in fibroblasts and colon cancer cells. However, its role in human cervical cancer is unclear. By immunohistochemical staining and Western blotting, aberrant Eps8 expression was observed in cervical carcinoma compared with normal cervical epithelial cells. Clinicopathologic analysis of 45 patients indicated that Eps8 expression was associated with parametrium invasion and lymph node metastasis, two major poor prognostic factors for early-stage cervical cancer. Kaplan-Meier analysis of cervical cancer specimens also indicated an inverse relationship between the level of Eps8 and the patients' survival rate. Using small interfering RNA of eps8, we observed reduced proliferation and tumorigenesis in Eps8-attenuated HeLa and SiHa cells cultured in dishes or inoculated in mice. Furthermore, diminished Eps8 impeded G₁-phase progression in HeLa and SiHa cells that might be attributable to reduced expression of cyclins D1, D3, and E, elevated accumulation of p53 and its downstream target p21^Waf1/Cip1, and suppressed hyperphosphorylation of retinoblastoma. Alteration of these cell cycle–related proteins could be reversed by ectopic Eps8, implicating that the effect of Eps8 on the mentioned cell cycle modulators was specific. Notably, the augmented expression of p53 by diminished Eps8 was at least due to its decreased turnover rate. Concurrent with p53 up-regulation and the decrement of Src and AKT activity, Eps8-attenuated HeLa and SiHa cells exhibited increased chemosensitivity to cisplatin and paclitaxel. Together, our findings implicate the involvement of Eps8 in chemoresistance and show its importance in prognosis of cervical cancer patients. [Mol Cancer Ther 2008;7(6):1376–85]

Grant support: China Medical University grant CMU95-306 (M-C. Maa) and National Health Research Institute grants NHRI-EX-96-9517BI and NHRI-EX-97-9517BI (T-H. Leu).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 12/11/07; revised 4/14/08; accepted 4/15/08.