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SOX4 Expression in Bladder Carcinoma: Clinical Aspects and In vitro Functional Characterization

¹ Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, and ² Department of Urology, Aarhus University Hospital/Skejby Sygehus, Aarhus N, Denmark; ³ Bioinformatics Research Center, University of Aarhus; ⁴ Institute of Pathology, Aarhus University Hospital, Aarhus Sygehus, Aarhus C, Denmark; and ⁵ Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Requests for reprints: Torben F. Ørntoft, Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital Skejby, 8200 Aarhus N, Denmark. Phone: 45-89495100; Fax: 45-89496018; E-mail: orntoft{at}ki.au.dk.

The human transcription factor SOX4 was 5-fold up-regulated in bladder tumors compared with normal tissue based on whole-genome expression profiling of 166 clinical bladder tumor samples and 27 normal urothelium samples. Using a SOX4-specific antibody, we found that the cancer cells expressed the SOX4 protein and, thus, did an evaluation of SOX4 protein expression in 2,360 bladder tumors using a tissue microarray with clinical annotation. We found a correlation (P < 0.05) between strong SOX4 expression and increased patient survival. When overexpressed in the bladder cell line HU609, SOX4 strongly impaired cell viability and promoted apoptosis. To characterize downstream target genes and SOX4-induced pathways, we used a time-course global expression study of the overexpressed SOX4. Analysis of the microarray data showed 130 novel SOX4-related genes, some involved in signal transduction (MAP2K5), angiogenesis (NRP2), and cell cycle arrest (PIK3R3) and others with unknown functions (CGI-62). Among the genes regulated by SOX4, 25 contained at least one SOX4-binding motif in the promoter sequence, suggesting a direct binding of SOX4. The gene set identified in vitro was analyzed in the clinical bladder material and a small subset of the genes showed a high correlation to SOX4 expression. The present data suggest a role of SOX4 in the bladder cancer disease. (Cancer Res 2006; 66(7): 3434-42)

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