Upregulation of TRAG3 gene in urothelial carcinoma of the bladder

Jose A. Karam, Sandra Huang, Jinhai Fan, Jennifer Stanfield, Roger A. Schultz, Rey Chen Pong, Xiankai Sun, Ralph P Mason, Xian-Jin Xie, Gang Niu, Xiaoyuan Chen, Eugene P Frenkel, Arthur I Sagalowsky, Jer-Tsong Hsieh

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Conventional chemotherapy is commonly used for advanced stages of bladder cancer with modest success and high morbidity. Identifying markers of resistance will allow clinicians to tailor treatment to a specific patient population. T24-tumorigenic cell line was grown orthotopically in nude mice and monitored using bioluminescence imaging and microcomputed tomography until they developed metastases. Stable sublines were then developed from primary bladder (T24-P), lung (T24-L) and bone (T24-B) tissues. Chromosomal analysis and DNA microarray were used to characterize these sublines. Real-time quantitative polymerase chain reaction and immunohistochemistry were used for validation. Epigenetic modifiers were used to study gene regulation. The cell viability was quantified with MTT assay. Chromosomal analysis revealed multiple alterations in metastatic cell lines compared to T24-P. DNA microarray analysis showed that taxol resistance-associated gene (TRAG) 3 was the most upregulated gene. From real-time quantitative polymerase chain reaction and immunohistochemistry, TRAG3 was significantly higher in T24-L and T24-B than T24-P. TRAG3 gene expression is likely controlled by DNA methylation but not histone acetylation. Interestingly, T24-B and T24-L cells were more resistant than T24-P to treatment with antimicrotubule agents such as docetaxel, paclitaxel and vinblastine. TRAG3 mRNA expression was higher in 20% of patients with ≤pT2 (n = 10) and 60% of patients with >pT3 (n = 20) compared to normal adjacent tissue (p = 0.05). In addition, the median TRAG3 expression was 6.7-fold higher in >pT3 tumors compared to a;circpT2 tumors. Knowing the status of TRAG3 expression could help clinicians tailor treatment to a particular patient population that could benefit from treatment, while allocating patients with resistant tumors to new experimental therapies.

Original languageEnglish (US)
Pages (from-to)2823-2832
Number of pages10
JournalInternational Journal of Cancer
Volume128
Issue number12
DOIs
Publication statusPublished - Jun 15 2011

    Fingerprint

Keywords

  • bladder
  • resistance
  • TRAG3
  • urothelial carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Karam, J. A., Huang, S., Fan, J., Stanfield, J., Schultz, R. A., Pong, R. C., ... Hsieh, J-T. (2011). Upregulation of TRAG3 gene in urothelial carcinoma of the bladder. International Journal of Cancer, 128(12), 2823-2832. https://doi.org/10.1002/ijc.25631