Human Molecular Genetics Advance Access originally published online on January 19, 2009
Human Molecular Genetics 2009 18(7):1343-1352; doi:10.1093/hmg/ddp034
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The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer
1 Lung Cancer Group, Molecular Pathology Programme 2 Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncologicas (CNIO), E-28029 Madrid, Spain 3 Programa de Oncologia Translacional, Instituto de Biologia Molecular y Celular del Cancer (CIC)—Consejo Superior de Investigaciones Cientificas (CSIC)—Universidad de Salamanca, Salamanca, Spain 4 Biology Division, National Cancer Center Research Institute, Tokyo, Japan 5 Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
* To whom correspondence should be addressed at: Cancer Epigenetics and Biology Program (PEBC), ICO-IDIBELL, Hospital Duran i Reynals, Av. Gran Via s/n km 2.7, 08907—L’Hospitalet de Llobregat, Barcelona, Spain. Tel: +34 932607500; Fax: +34 932607219; Email: mscespedes{at}iconcologia.net
Received October 8, 2008; Accepted January 15, 2009
The search for oncogenes is becoming increasingly important in cancer genetics because they are suitable targets for therapeutic intervention. To identify novel oncogenes, activated by gene amplification, we analyzed cDNA microarrays by high-resolution comparative genome hybridization and compared DNA copy number and mRNA expression levels in lung cancer cell lines. We identified several amplicons (5p13, 6p22-21, 11q13, 17q21 and 19q13) that had a concomitant increase in gene expression. These regions were also found to be amplified in lung primary tumours. We mapped the boundaries and measured expression levels of genes within the chromosome 6p amplicon. The Sry-HMG box gene SOX4 (sex-determining region Y box 4), which encodes a transcription factor involved in embryonic cell differentiation, was overexpressed by a factor of 10 in cells with amplification relative to normal cells. SOX4 expression was also stronger in a fraction of lung primary tumours and lung cancer cell lines and was associated with the presence of gene amplification. We also found variants of SOX4 in lung primary tumours and cancer cell lines, including a somatic mutation that introduced a premature stop codon (S395X) at the serine-rich C-terminal domain. Although none of the variants increased the transactivation ability of SOX4, overexpression of the wildtype and of the non-truncated variants in NIH3T3 cells significantly increased the transforming ability of the weakly oncogenic RHOA-Q63L. In conclusion, our results show that, in lung cancer, SOX4 is overexpressed due to gene amplification and provide evidence of oncogenic properties of SOX4.
The data discussed in this publication have been deposited in NCBIs Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession number GSE14079
[NCBI GEO]
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Present address: Department of Molecular, Cellular and Developmental Biology, Yale University KBT 938, 266 Whitney Ave., New Haven, 06520 CT, USA.