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Identification of GRP75 as an Independent Favorable Prognostic Marker of Neuroblastoma by a Proteomics Analysis

Authors' Affiliations: Departments of ¹ Surgery, ² Pathology, and ³ Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine; ⁴ Department of Life Science and Institutes of ⁵ Zoology and ⁶ Molecular and Cellular Biology, National Taiwan University; ⁷ Institute of Cellular and Organismic Biology, Academia Sinica; ⁸ Institute of Biochemistry and Molecular Biology and Proteomics Research Center, National Yang-Ming University; and ⁹ Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

Requests for reprints: Fon-Jou Hsieh, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei 100, Taiwan. Phone: 886-2-23562614; Fax: 886-2-23934197; E-mail: fjhsieh{at}ntu.edu.tw.

Purpose: Neuroblastoma (NB) is a heterogeneous neoplasm. Detailed biological discrimination is critical for the effective treatment of this disease. Because the tumor behavior of NB is closely associated with the histologic state of differentiation, we thus aimed to identify novel differentiation-associated markers of NB with prognostic implication.

Experimental Design: A human NB cell line SH-SY5Y was used as a model system to explore potential biomarkers for the differentiation of NB by proteomic analyses. Seventy-two NB tumor tissues were subsequently investigated by immunohistochemistry to validate the correlations between the expression of a novel prognostic marker, various clinicopathologic and biological factors, and patient survival.

Results: Using two-dimensional differential gel electrophoresis, we found a total of 24 spots of proteins in SH-SY5Y cells whose expression was enhanced following differentiation. Glucose-regulated protein 75 (GRP75) was unambiguously identified as one of the five proteins that were dramatically up-regulated following differentiation. Immunohistochemical analyses of 72 NB tumor tissues further revealed that positive GRP75 immunostaining is strongly correlated with differentiated histologies (P < 0.001), mass-screened tumors (P = 0.016), and early clinical stages (P < 0.001) but inversely correlated with MYCN amplification (P = 0.010). Univariate and multivariate survival analyses showed that GRP75 expression is an independent favorable prognostic factor.

Conclusions: The present findings clearly showed that our proteomics-based novel experimental paradigm could be a powerful tool to uncover novel biomarkers associated with the differentiation of NB. Our data also substantiate an essential role of GRP75 in the differentiation of NB.