Upregulation of Tissue and Urinary Nicotinamide N-Methyltransferase in Bladder Cancer: Potential for the Development of a Urine-Based Diagnostic Test

Abstract

Carcinoma of the bladder is one of the most common urologic malignancies occurring worldwide. Diagnosis and monitoring of bladder urothelial carcinoma (UC) are based on cystoscopy and urinary cytology. However, these diagnostic methods still have some limitations, mainly related to invasive nature and lack of sensitivity. New reliable and non-invasive biomarkers for bladder cancer detection are therefore required. To explore the involvement of enzymes of drug metabolism in bladder cancer, in the present study, we analyzed the gene expression profiles of tumor and normal looking tissues obtained from the same patient by cDNA macroarray. The enzyme nicotinamide N-methyltransferase (NNMT) was identified as a highly expressed gene in bladder cancer. RT-PCR, Real-Time PCR, Western blot analysis, and catalytic activity assay, performed on a large cohort of patients with bladder UC, confirmed NNMT upregulation. NNMT mRNA and protein levels were also determined in urine specimens obtained from patients with bladder UC and healthy subjects. We found that NNMT expression levels were significantly higher in patients with bladder tumor compared to controls that showed very low or undetectable amounts of NNMT transcript and protein. Our results indicate that a marked NNMT increase is a peculiar feature of bladder UC and suggest the potential suitability of urine NNMT expression levels determination for early and non-invasive diagnosis of bladder cancer.

Identification and Characterization of Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma Cell Lines

“…An enhanced expression of NNMT has been reported in a number of cancers, such as glioblastoma [47], stomach adenocarcinoma [48,49], papillary thyroid cancers [50,51], renal [52,53], and oral squamous cell carcinomas [54][55][56], colorectal cancer [57], bladder [58], lung and pancreatic cancers [59][60][61]. In our previous works, we explored NNMT expression in renal cell carcinoma (ccRCC) [52], oral squamous cell carcinoma (OSCC) [54][55][56], urothelial carcinoma (UC) of the bladder [58] and non-small cell lung cancer (NSCLC) [60]. Although several cancers have been associated with abnormal NNMT expression, its role in cancer cell metabolism remains largely unknown.…”

Effects of Nicotinamide N-Methyltransferase on PANC-1 Cells Proliferation, Metastatic Potential and Survival Under Metabolic Stress

“…As a phase II metabolizing enzyme, NNMT is involved in the biotransformation of many drugs and xenobiotic compounds [6,7,21]. Abnormal NNMT expression has been reported in many human neoplasms including brain, nasopharynx, oral cavity, thyroid, lung, liver, stomach, kidney, bladder and colon [8,9,10,11,12,13,14,15,16,17,18]. Furthermore, a recent study showed that NNMT overexpression was associated with increased radioresistance via regulating nicotinamide metabolism [22].…”

“…It is predominantly expressed in liver and weakly expressed in other tissues like kidney, lung, skeletal muscle, placenta, heart and brain [6]. Abnormal expression of NNMT has been found in numerous cancers, including glioblastoma [8], hepatocellular carcinoma [9], thyroid carcinoma [10], gastric cancer [11], renal cell carcinoma [12], colorectal cancer [13], oral squamous cell carcinoma [14], bladder cancer [15], non-small cell lung cancer [16], and nasopharyngeal carcinoma [17]. These results suggest that NNMT may serve as a potential biomarker for tumor diagnosis and a new therapeutic target.…”

Role of nicotinamide N-methyltransferase in non-small cell lung cancer: in vitro effect of shRNA-mediated gene silencing on tumourigenicity

“…NNMT is reported to be overexpressed in many neoplasms. In our previous works, we analysed NNMT expression levels in renal cell carcinoma (RCC) ( Sartini et al, 2006 ), in oral squamous cell carcinoma (OSCC) ( Sartini et al, 2007( Sartini et al, , 2012Emanuelli et al, 2010 ), in bladder urothelial carcinoma (BUC) ( Sartini et al, 2013a ) and in NSCLC ( Sartini et al, 2013b ).…”