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The Prognostic and Therapeutic Relevance of p27^kip1 in Ewing’s Family Tumors

¹ Departments of Orthopaedic Surgery and ² Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, and ³ First Department of Internal Medicine, Gunma University, Gunma, Japan

Purpose: Ewing’s family tumors (EFTs) display the characteristic fusion gene EWS-Fli1. We have reported EWS-Fli1 may promote the cell cycle progression accompanied by the suppression of the expression of cyclin-dependent kinase inhibitor p27^kip1 in EFT cells. Here, we describe the prognostic and therapeutic relevance of p27 in EFTs.

Experimental Design: We examined tumor samples taken from 21 patients with primary EFTs for the expression of p27 protein immunohistochemically and evaluated its correlation with clinical outcome. We also investigated the usefulness of p27 as a therapeutic strategy in vitro and in vivo using p27 expression adenovirus. Finally, we examined the process of EWS-Fli1-mediated reduction of p27 expression.

Results: Immunohistochemical analysis showed that a low expression level of p27 protein was related to poor event-free survival in an univariate analysis and that the expression level of p27 correlated more significantly with patient survival than several clinical factors in a multivariate survival analysis. Overexpression of p27 with the adenoviral vector remarkably inhibited the cell growth in all EFT cells tested and further induced apoptosis in the wild-type p53 EFT cells. In vivo studies demonstrated a reduction in tumor growth of EFT xenograft in nude mice treated with the intratumoral injection of p27-expressing adenovirus. EWS-Fli1 did not significantly affect the p27 promoter activity and p27 mRNA levels. However, the challenge of the proteasome inhibitor caused accumulation of p27 protein in EFT cells. These data strongly suggest EWS-Fli1 might attenuate p27 protein level via activation of the proteasome-mediated degradation pathway.

Conclusions: Our findings provide the first evidence of the prognostic relevance of p27 expression in EFTs. We propose p27 as a novel and powerful therapeutic factor for the molecular target therapy of EFTs.

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