The prognostic and therapeutic relevance of p27kip1 in Ewing's family tumors.

Abstract

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.

• Authors: Tomoya Matsunobu, Kazuhiro Tanaka, Yoshihiro Matsumoto, Fumihiko Nakatani, Riku Sakimura, Masuo Hanada, Xu Li, Yoshinao Oda, Ichiro Naruse, Hideki Hoshino, Masazumi Tsuneyoshi, Hiromasa Miura, Yukihide Iwamoto
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 3 Pg. 1003-12 (Feb 01 2004) ISSN: 1078-0432 [Print] United States
• PMID: 14871979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cdkn1b protein, mouse
• Cell Cycle Proteins
• Multienzyme Complexes
• Oligonucleotides
• RNA, Messenger
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• Luciferases
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex

Topics

• Adenoviridae (genetics)
• Adolescent
• Adult
• Aged
• Animals
• Apoptosis
• Blotting, Western
• Cell Cycle
• Cell Cycle Proteins (biosynthesis, genetics)
• Cell Line, Tumor
• Child
• Cyclin-Dependent Kinase Inhibitor p27
• Cysteine Endopeptidases (metabolism)
• DNA Fragmentation
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Female
• Humans
• Immunohistochemistry
• Luciferases (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Multienzyme Complexes (metabolism)
• Multivariate Analysis
• Neoplasm Transplantation
• Oligonucleotides (chemistry)
• Prognosis
• Promoter Regions, Genetic
• Proteasome Endopeptidase Complex
• Protein Processing, Post-Translational
• RNA, Messenger (metabolism)
• Recurrence
• Reverse Transcriptase Polymerase Chain Reaction
• Sarcoma, Ewing (diagnosis, genetics, mortality)
• Time Factors
• Treatment Outcome
• Tumor Suppressor Protein p53 (metabolism)
• Tumor Suppressor Proteins (biosynthesis, genetics)