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Cathepsin D Is a Potential Serum Marker for Poor Prognosis in Glioma Patients

Departments of ¹ Neurological Surgery, ² Biochemistry and Genetics, ³ Functional Genomics, ⁴ Molecular Pathology, and ⁵ Clinical Molecular Biology, Chiba University Graduate School of Medicine, Chiba, Japan

Requests for reprints: Yasuo Iwadate, Department of Neurological Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, 260-8670 Chiba, Japan. Phone: 81-43-226-2158; Fax: 81-43-226-2159; E-mail: iwadatey{at}faculty.chiba-u.jp.

Cathepsin D is an aspartyl protease involved in protein catabolism and tissue remodeling which can be secreted from cancer cells. To identify a potential serum marker for gliomas, we investigated the gene expression levels of cathepsin D in 87 tissue samples and measured the protein concentrations in sera of glioma patients. The tissue samples consisted of 43 glioblastomas, 13 anaplastic astrocytomas, 22 astrocytomas, and 9 normal brain tissues. The results of real-time quantitative reverse transcription-PCR analysis showed that cathepsin D transcript levels became significantly higher as the glioma grade advanced (P = 0.0466, glioblastoma and anaplastic astrocytoma; P = 0.0008, glioblastoma and astrocytoma; P = 0.0271, glioblastoma and normal brain tissue; unpaired t test). Immunohistochemical analysis with anti-cathepsin D antibody revealed dense and spotty staining in the tumor cells with high transcript levels. The low expression of cathepsin D significantly correlated with long survival of the glioma patients. Furthermore, the glioblastoma patients with high gene expression of cathepsin D lived significantly shorter than those with low expression (P = 0.0104, Cox-Mantel log-rank test) and frequently had leptomeningeal dissemination (P = 0.0016, ² test). The multivariate analysis confirmed that the cathepsin D expression level was an independent predictor for short survival (P = 0.0102, Cox proportional hazard regression model). Measurement of the serum cathepsin D concentrations by ELISA showed a significant increase in the patients with high-grade gliomas as compared with the low-grade tumors (P = 0.0081, ² test). These results collectively suggest that cathepsin D could be a potential serum marker for the prediction of aggressive nature of human gliomas.

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