SOX4 expression in bladder carcinoma: clinical aspects and in vitro functional characterization.
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.
Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital/Skejby Sygehus, 8200 Aarhus N, Denmark.
Mads
M
Aaboe
Karin
K
Birkenkamp-Demtroder
Carsten
C
Wiuf
Flemming Brandt
FB
Sørensen
Thomas
T
Thykjaer
Guido
G
Sauter
Klaus Møller-Ernst
KM
Jensen
Lars
L
Dyrskjøt
Torben
T
Ørntoft
D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006609:High Mobility Group Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D055751:SOXC Transcription Factors; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism*
D006609:High Mobility Group Proteins; D012333:RNA, Messenger; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D015534:Trans-Activators