Identification of Gene Expression Signature Modulated by Nicotinamide in a Mouse Bladder Cancer Model

BACKGROUND: Urinary bladder cancer is often a result of exposure to chemical carcinogens such as cigarette smoking. Because of histological similarity, chemically-induced rodent cancer model was largely used for human bladder cancer studies. Previous investigations have suggested that nicotinamide, water-soluble vitamin B3, may play a key role in cancer prevention through its activities in cellular repair. However, to date, evidence towards identifying the genetic alterations of nicotinamide in cancer prevention has not been provided. Here, we search for the molecular signatures of cancer prevention by nicotinamide using a N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced urinary bladder cancer model in mice. METHODOLOGY/PRINCIPAL FINDINGS: Via microarray gene expression profiling of 20 mice and 233 human bladder samples, we performed various statistical analyses and immunohistochemical staining for validation. The expression patterns of 893 genes associated with nicotinamide activity in cancer prevention were identified by microarray data analysis. Gene network analyses of these 893 genes revealed that the Myc and its associated genes may be the most important regulator of bladder cancer prevention, and the gene expression signature correlated well with protein expression data. Comparison of gene expression between human and mouse revealed that BBN-induced mouse bladder cancers exhibited gene expression profiles that were more similar to those of invasive human bladder cancers than to those of non-invasive human bladder cancers. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that nicotinamide plays an important role as a chemo-preventive and therapeutic agent in bladder cancer through the regulation of the Myc oncogenic signature. Nicotinamide may represent a promising therapeutic modality in patients with muscle-invasive bladder cancer

Assess the expression of ubiquitin specific protease USP2a for bladder cancer diagnosis

Background: Given that a deubiquitinating enzyme, ubiquitin-specific protease 2a (USP2a), regulates ubiquitination, trafficking, and degradation of EGFR, which plays a critical role in bladder cancer, in this study, we aimed to quantify the USP2a gene expression, and to determine the possibility that USP2a can be used for bladder cancer diagnosis. Methods: Using two independent cohorts (cohort 1, n = 339 in total; cohort 2, n = 140 in total) consisting of human bladder tissues from BC patients and normal controls, we analyzed the gene expression levels of USP2a. A quantitative real-time PCR amplification was performed using a Rotor Gene 6000 instrument to quantify the expression of USP2a mRNA. Results: A comparison of 305 bladder cancers and 34 age-matched controls showed an 81.4 % reduction in USP2a expression in bladder cancers as compared to normal bladder tissues (p < 0.001). In the independent cohort consisting of 140 BC tissues and matched adjacent normal bladder tissues, the levels of USP2a in the specimens of BC patients were reduced by 86.9 % as compared to matched surrounding normal specimens from the same patients (p < 0.001). Furthermore, there was 36.3 % reduction of USP2a gene expression in muscle invasive bladder cancer (MIBC, n = 121), compared to non muscle invasive bladder cancer (NMIBC, n = 184) (p = 0.004). Lastly, USP2a mRNA expression was significantly reduced in higher stages of MIBC patients (p = 0.024), but not in NMIBC patients. Conclusions: Our findings suggest that USP2a mRNA may be considered as a diagnostic marker candidate for bladder cancer, in particular, to stratify MIBC patients with a more invasive phenotype

Identification of C16orf74 as a Marker of Progression in Primary Non-Muscle Invasive Bladder Cancer

PURPOSE: Methylation-induced silencing of PRSS3 has been shown to be significantly associated with invasive bladder cancer, and expression of the C16orf74 gene locus has been shown to correlate positively with PRSS3. The aim of the current study was to evaluate the relationship between C16orf74 expression level and progression in non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: C16orf74 mRNA levels were examined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis of 193 tumor specimens from patients with primary NMIBC. Expression data were analyzed in terms of clinical and experimental parameters. Kaplan-Meier curves and multivariate Cox regression models, respectively, were used to determine progression-free survival and to identify independent predictive parameters of progression. RESULTS: Analysis using Kaplan-Meier curves revealed prolonged progression-free survival of high-C16orf74-expressors as compared to low-expressors (p<0.001). Multivariate Cox regression analysis revealed that low C16orf74 mRNA expression levels are a significant risk factor for disease progression in patients with primary NMIBC (HR: 10.042, CI:2.699-37.360, p = 0.001). CONCLUSIONS: Decreased expression of C16orf74 correlates significantly with progression in primary NMIBC. C16orf74 expression level represents a potentially useful marker for predicting progression in primary NMIBC patients

Alpha-Methylacyl-Coenzyme A Racemase-Expressing Urachal Adenocarcinoma of the Abdominal Wall

Urachal adenocarcinomas are very rare and about one third of these neoplasms arise in urachal remnants. To demonstrate the origin of the urachal adenocarcinoma is not easy, but it is very important for managing patient care. We report on a 35-year-old man who complained of a palpable mass in the periumbilical area. The mass was incidentally identified 10 days earlier. Computed tomography revealed a well-defined enhancing mass with internal calcification and septation abutting on the dome of the urinary bladder. The clinical diagnosis was urachal cancer, which seemed to invade the urinary bladder. Thus, we performed mass excision and partial resection of the bladder. Histopathologically, the mass was diagnosed as mucinous cystadenocarcinoma originating from urachal remnants that showed an unusual expression of alpha-methylacyl-coenzyme A racemase (AMACR). To our knowledge, this report is the first case of AMACR-expressing urachal adenocarcinoma arising in the abdominal wall

Decreased DBC1 Expression Is Associated With Poor Prognosis in Patients With Non-Muscle-Invasive Bladder Cancer

Purpose The deleted in bladder cancer 1 (DBC1) gene is located within chromosome 9 (9q32-33), a chromosomal region that frequently shows loss of heterozygosity in bladder cancer (BC). It is suspected that it acts as a tumor suppressor gene, but its prognostic value remains unclear. The aim of the present study was to investigate the value of DBC1 as a prognostic marker in BC. Materials and Methods The expression of DBC1 was determined by real-time polymerase chain reaction analysis in 344 patients with BC (220 non-muscle-invasive BC [NMIBC] and 124 muscle-invasive BC [MIBC]) and in 34 patients with normal bladder mucosa. The results were compared with clinicopathologic parameters, and the prognostic value of DBC1 was evaluated by Kaplan-Meier analysis and a multivariate Cox regression model. Results: DBC1 expression was significantly decreased in patients with MIBC compared with those diagnosed with NMIBC (p=0.010). Patients with aggressive tumor characteristics had lower DBC1 expression levels in NMIBC (each, p<0.05). By multivariate Cox regression analysis, low DBC1 expression was a predictor of progression to MIBC (hazard ratio, 7.104; p=0.013). Kaplan-Meier estimates revealed a significant difference in tumor recurrence, progression to MIBC, and cancer-specific survival depending on the level of DBC1 expression in NMIBC (log-rank test, each, p<0.05). Conclusions: The expression of DBC1 was associated with tumor aggressiveness, progression to MIBC, and survival in NMIBC. Our results suggest that DBC1 expression can be a useful prognostic marker for patients with NMIBC

Granular Cell Tumor of the Urinary Bladder

A 67-year-old Korean man presented with gross, painless hematuria that had lasted for the previous 2 months. Cystoscopy showed a semispherical tumor approximately 1 cm in diameter that was covered with normal bladder mucosa and extended from the bladder neck to the posterior wall of the bladder. The patient underwent transurethral resection of the tumor. Histological examination and immunohistochemical staining showed a granular cell tumor (GCT). There were no features suggesting a malignant phenotype. On follow-up, the patient has remained free of bladder recurrence. We herein report this case of a GCT of the urinary bladder and review the literature

Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer

<p>Abstract</p> <p>Background</p> <p>While several molecular markers of bladder cancer prognosis have been identified, the limited value of current prognostic markers has created the need for new molecular indicators of bladder cancer outcomes. The aim of this study was to identify genetic signatures associated with disease prognosis in bladder cancer.</p> <p>Results</p> <p>We used 272 primary bladder cancer specimens for microarray analysis and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Microarray gene expression analysis of randomly selected 165 primary bladder cancer specimens as an original cohort was carried out. Risk scores were applied to stratify prognosis-related gene classifiers. Prognosis-related gene classifiers were individually analyzed with tumor invasiveness (non-muscle invasive bladder cancer [NMIBC] and muscle invasive bladder cancer [MIBC]) and prognosis. We validated selected gene classifiers using RT-PCR in the original (165) and independent (107) cohorts. Ninety-seven genes related to disease progression among NMIBC patients were identified by microarray data analysis. Eight genes, a progression-related gene classifier in NMIBC, were selected for RT-PCR. The progression-related gene classifier in patients with NMIBC was closely correlated with progression in both original and independent cohorts. Furthermore, no patient with NMIBC in the good-prognosis signature group experienced cancer progression.</p> <p>Conclusions</p> <p>We identified progression-related gene classifier that has strong predictive value for determining disease outcome in NMIBC. This gene classifier could assist in selecting NMIBC patients who might benefit from more aggressive therapeutic intervention or surveillance.</p