Int J Biol Sci 2015; 11(12):1363-1375. doi:10.7150/ijbs.13240 This issue

Research Paper

Sox4 Expression Confers Bladder Cancer Stem Cell Properties and Predicts for Poor Patient Outcome

He Shen1#, Maxime Blijlevens1,4#, Nuo Yang1, Costakis Frangou1, Kayla E. Wilson1, Bo Xu2, Yinglong Zhang1,5, Lirui Zhang1,6, Carl D. Morrison2, Lori Shepherd3, Qiang Hu3, Qianqian Zhu3, Jianmin Wang3, Song Liu3, Jianmin Zhang1,✉

1. Department of Cancer Genetics;
2. Department of Pathology;
3. Center for Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo NY 14263;
4. VU medical center, Cancer Center Amsterdam, Laboratory Medical Oncology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands;
5. Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China;
6. Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China.
# Equal contribution

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See for full terms and conditions.
Shen H, Blijlevens M, Yang N, Frangou C, Wilson KE, Xu B, Zhang Y, Zhang L, Morrison CD, Shepherd L, Hu Q, Zhu Q, Wang J, Liu S, Zhang J. Sox4 Expression Confers Bladder Cancer Stem Cell Properties and Predicts for Poor Patient Outcome. Int J Biol Sci 2015; 11(12):1363-1375. doi:10.7150/ijbs.13240. Available from

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Graphic abstract

Genetic and epigenetic alterations have been identified as to contribute directly or indirectly to the generation of transitional cell carcinoma of the urinary bladder (TCC-UB). We have previously found that amplification of chromosome 6p22 is significantly associated with the muscle-invasive rather than superficial TCC-UB. Here, we demonstrated that Sox4, one of the candidate oncogenes located within the chromosome 6p22 amplicon, confers bladder cancer stem cell (CSC) properties. Down-regulation of Sox4 led to the inhibition of cell migration, colony formation as well as mesenchymal-to-epithelial transition (MET). Interestingly, knockdown of Sox4 also reduced the sphere formation, enriched cell population with high levels of aldehyde dehydrogenase (ALDH high) and tumor formation potential. Using gene expression profiling, we further identified novel Sox4 target genes. Last, immunohistochemistry analysis of human bladder tumor tissue microarrays (TMAs) indicated that high Sox4 expression was correlated with advanced cancer stages and poor survival rate. In summary, our data show that Sox4 is an important regulator of the bladder CSC properties and it may serve as a biomarker of the aggressive phenotype in bladder cancer.

Keywords: bladder cancer, chromosome 6p22 amplification, Sox4, bladder cancer stem cell