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Chen Y.-T.,Chang Gung University | Chen H.-W.,Chang Gung University | Domanski D.,University of Victoria | Smith D.S.,University of Victoria | And 9 more authors.
Journal of Proteomics

Three common urological diseases are bladder cancer, urinary tract infection, and hematuria. Seventeen bladder cancer biomarkers were previously discovered using iTRAQ - these findings were verified by MRM-MS in this current study. Urine samples from 156 patients with hernia (n = 57, control), bladder cancer (n = 76), or urinary tract infection/hematuria (n = 23) were collected and subjected to multiplexed LC-MRM/MS to determine the concentrations of 63 proteins that are normally considered to be plasma proteins, but which include proteins found in our earlier iTRAQ study. Sixty-five stable isotope-labeled standard proteotypic peptides were used as internal standards for 63 targeted proteins. Twelve proteins showed higher concentrations in the bladder cancer group than in the hernia and the urinary tract infection/hematuria groups, and thus represent potential urinary biomarkers for detection of bladder cancer. Prothrombin had the highest AUC (0.796), with 71.1% sensitivity and 75.0% specificity for differentiating bladder cancer (n = 76) from non-cancerous (n = 80) patients. The multiplexed MRM-MS data was used to generate a six-peptide marker panel. This six-peptide panel (afamin, adiponectin, complement C4 gamma chain, apolipoprotein A-II precursor, ceruloplasmin, and prothrombin) can discriminate bladder cancer subjects from non-cancerous subjects with an AUC of 0.814, with a 76.3% positive predictive value, and a 77.5% negative predictive value. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry. © 2012 Elsevier B.V.. Source

Wu C.-F.,Chia Yi Chang Gung Memorial Hospital | Wu C.-F.,Chang Gung University | Ng K.-F.,Lin Kou Chang Gung Memorial Hospital | Chen C.-S.,Chia Yi Chang Gung Memorial Hospital | And 7 more authors.
British Journal of Cancer

Background:Parvin-Β (ParvB), a potential tumour suppressor gene, is a focal adhesion protein. We evaluated the role of ParvB in the upper urinary tract urothelial cell carcinoma (UUT-UC).Methods:ParvB mRNA and proteins levels in UUT-UC tissue were investigated by quantitative real-time polymerase chain reaction and western blot analysis, respectively. In addition, the expression of ParvB in tissues from patients with UUT-UC at different stages was evaluated by immunohistochemistry. Furthermore, biological functions of ParvB in urothelial cancer cells were investigated using a doxycycline-inducible overexpression system and siRNA.Results:Western blot and mRNA analysis showed downregulation of ParvB expression in frozen UUT-UC tissue. Immunohistochemistry revealed high staining intensity of ParvB in normal urothelium, which decreased markedly at advanced stages of UUT-UC (P0.0000). Moreover, ParvB was an independent prognostic indicator for disease-specific survival of patients with UUT-UC. Functional assays indicated that overexpression of ParvB in an urothelial cancer cell line resulted in decreased cell growth rate and ability to migrate. In contrast, knockdown of ParvB expression increased cell migration ability.Conclusions:Downregulation of ParvB expression significantly increased urothelial cancer cell growth and migration. Downexpression of ParvB level in UUT-UC correlated with tumour stage, and was an independent unfavourable prognostic factor for disease-specific survival of patients with UUT-UC. © 2010 Cancer Research UK All rights reserved. Source

Tsui K.-H.,Chang Gung Bioinformatics Center | Tang P.,Chang Gung Bioinformatics Center | Lin C.-Y.,Chang Gung University | Chang P.-L.,Chang Gung Bioinformatics Center | And 2 more authors.
Journal of Urology

Purpose: We searched for bladder tumor markers by analyzing urine samples from patients with bladder cancer and normal individuals. Materials and Methods: Proteins in urine samples of patients with cancer and normal subjects were systematically examined by 2-dimensional electrophoresis combined with matrix assisted laser desorption ionization time-of-flight mass spectrometry. Of the proteins bikunin expression was confirmed by Western blot analysis and further evaluated. To correlate urinary bikunin levels with clinical significance we examined urine samples from patients with bladder cancer and normal controls for bikunin expression in parallel with pro-urolinase-plasminogen activator, which was previously shown to be associated with advanced bladder carcinoma. Results: A significant relationship was established between the low level and absence of bikunin, and pro-urolinase-plasminogen activator in urine samples from patients with bladder tumors. Conclusions: Analysis of urinary proteomes may be a feasible, noninvasive and efficient strategy for searching for potential bladder tumor biomarkers. We identified bikunin loss in urine as a potential bladder carcinoma marker. © 2010 American Urological Association. Source

Tsui K.-H.,Chang Gung Memory Hospital | Tsui K.-H.,Chang Gung Bioinformatics Center | Lin Y.-F.,Chang Gung University | Chen Y.-H.,Chang Gung University | And 4 more authors.
Journal of Andrology

Interleukin-6 (IL-6) is involved in regulation of cell growth and survival of prostate carcinoma cells. Previous studies suggest that IL-6 promotes prostate cancer progression through the induction of an androgen-independent response. In this study, we evaluated the mechanisms by which IL-6 regulates the gene expression of prostate-specific antigen (PSA) in human prostate LNCaP carcinoma cells. 3H-thymidine incorporation assays revealed that IL-6 treatment inhibited the proliferation of LNCaP cells. Results of enzyme-linked immunosorbent assay (ELISA) and immunoblot assays indicated that IL-6 treatment enhanced PSA gene expression. Similar results were found in LNCaP cells that had been engineered to stably overexpress IL-6. Although forced overexpression of c-Myc-associated zinc finger protein (MAZ) induced PSA promoter activity, mutation of the MAZ response elements had little effect on IL-6-induced PSA promoter activity. Results from 59-deletion reporter assays revealed that the effects of IL-6 appear to be mediated via an androgen enhancer region (24801 to 23933), which is dependent on the signal transducer and activator of the transcription 3 (STAT3) pathway, and a region located at 2193 to 241 base pairs upstream of the translational initiation site of the human PSA gene, which did not respond to androgen or STAT3. Results of reporter assays, immunoblot assays, and ELISA revealed that the heat shock protein 90 (Hsp90) inhibitors 17-allyamino-17-demethoxygeldanamycin and geldanamycin blocked IL-6-induced PSA gene expression. Those results suggest that IL-6 upregulates PSA gene expression and that Hsp90 plays a novel role in the activation of IL-6 on PSA gene expression in an androgenindependent manner. © American Society of Andrology. Source

Wu C.-F.,Chia Yi Chang Gung Memorial Hospital | Wu C.-F.,Chang Gung University | Pang S.-T.,Chang Gung University | Shee J.-J.,Chia Yi Chang Gung Memorial Hospital | And 6 more authors.
Genes Chromosomes and Cancer

Clinical presentations of end-stage renal disease (ESRD) patients on dialysis with upper urinary tract urothelial carcinoma (UUT-UC) are different from those with normal renal function. The pathogenesis remains unknown. We investigated the pathogenetic influence of chromosomal aberrations in patient on dialysis with UUT-UC. The chromosomal aberrations of UUT-UC specimens from seven dialysis patients were assessed by conventional comparative genomic hybridization (cCGH). Subsequently, we further investigated 20 cases by whole genome and fine-tiling oligonucleotide array-based CGH to demonstrate gains and losses, and compared with the clinicopathologic background. The chromosomal aberrations in UUT-UC specimens from dialysis patients were more complex than in bladder urothelial carcinoma (B-UC). Our data showed that gains at 5p, 7, 19q, and losses at 4q, 9p, and 15q are common in UUT-UC of ESRD patients. Gains in regions associated with DNA repair genes were noted in this study. High-stage and high-grade tumors displayed more copy number variants. In addition, female ESRD patients with UUT-UC had more frequent chromosomal aberrations than their male counterparts. In conclusion, unique chromosomal aberrations were indentified in UUT-UC in ESRD patients. © 2010 Wiley-Liss, Inc. Source

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