title: Upregulation of TRAG3 gene in urothelial carcinoma of the bladder.
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 ≤ pT2 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.
authors: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9110, USA.
authors: Jose A
authors: JA
authors: Karam
authors: Sandra
authors: S
authors: Huang
authors: Jinhai
authors: J
authors: Fan
authors: Jennifer
authors: J
authors: Stanfield
authors: Roger A
authors: RA
authors: Schultz
authors: Rey-Chen
authors: RC
authors: Pong
authors: Xiankai
authors: X
authors: Sun
authors: Ralph P
authors: RP
authors: Mason
authors: Xian-Jin
authors: XJ
authors: Xie
authors: Gang
authors: G
authors: Niu
authors: Xiaoyuan
authors: X
authors: Chen
authors: Eugene P
authors: EP
authors: Frenkel
authors: Arthur I
authors: AI
authors: Sagalowsky
authors: Jer-Tsong
authors: JT
authors: Hsieh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001483:Base Sequence; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C118809:CSAG2 protein, human; D017931:DNA Primers; D009363:Neoplasm Proteins