Analysis of tissue and salivary nicotinamide N-methyltransferase in oral squamous cell carcinoma: basis for the development of a noninvasive diagnostic test for early-stage disease

Abstract

Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer worldwide. In recent decades, the 5-year mortality rate is approximately 50% around the world. As reliable biomarkers of oral cancer are still lacking, it is necessary to identify new target molecules for early diagnosis, effective therapy, and monitoring of the disease. In the present work, we focused on the expression of the enzyme nicotinamide N-methyltransferase (NNMT). We analyzed enzyme activity in 37 paired tumor and non-tumor tissues and found that activity levels are significantly higher in tumor compared with adjacent normal oral mucosa. Interestingly, oral epithelium surrounding tumor of unfavorable cases (N+) seems to display higher activity levels compared with that of favorable ones (N0). Western blot analyses were performed to evaluate protein levels in saliva samples from patients with OSCC and healthy subjects. Preliminary results indicated an up-regulation of salivary NNMT in tumor. This study shows a marked increase in enzyme activity in oral cancer and suggests that adjacent normal tissue of unfavorable cases seems to change toward cancer. Moreover, it is conceivable to hypothesize that NNMT could represent a potential biomarker for early and non-invasive diagnosis of oral 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.…”

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

“…NNMT is mainly expressed in the liver, along with reduced expression levels in the kidney, lung, skeletal muscle, placenta, heart, bladder and brain ( Aksoy et al, 1994 ). NNMT upregulation has been reported in several neoplasms, such as glioblastoma multiforme ( Markert et al, 2001 ), gastric cancer ( Lim et al, 2006 ), papillary thyroid cancer ( Xu et al, 2003 ), RCC ( Sartini et al, 2006 ), OSCCs ( Sartini et al, 2007 ;Emanuelli et al, 2010 ;Sartini et al, 2012 ), colorectal ( Roessler et al, 2005 ), bladder ( Sartini et al, 2013a ), lung ( Sartini et al, 2013b ), and pancreatic ( Rogers et al, 2006 ) cancers. Moreover, NNMT was found to be overexpressed in atherosclerosis ( Mateuszuk et al, 2009 ), chronic obstructive pulmonary disease (COPD) ( Debigar é et al, 2008 ), and Parkinson ' s disease ( Parsons et al, 2002 ).…”

“…In OSCC, NNMT overexpression inversely correlated with pT, lymph node metastasis, pathological staging, and histological grading, suggesting that the enzyme could play an important role in tumour expansion and differentiation, and may have a potential as prognostic marker ( Sartini et al, 2007 ;Emanuelli et al, 2010 ). In addition, we reported an overexpression of salivary and urinary NNMT in OSCC and BUC, respectively, indicating that the enzyme could represent a potential biomarker for early and noninvasive diagnosis of these malignancies ( Sartini et al, 2012( Sartini et al, , 2013a. Moreover, NNMT knockdown led to reduced tumorigenicity of KB and PE/CA-PJ15 cancer cells, suggesting the possibility of the enzyme as a molecular target for anti-cancer therapy ( Pozzi et al, , 2013.…”

“…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 ).…”

Nicotinamide N-methyltransferase is overexpressed in prostate cancer and correlates with prolonged progression-free and overall survival times

“…Previous studies have revealed the abnormal expression of NNMT in a number of cancers, and this may contribute to tumor development and progression, as well as resistance to radiotherapy and chemotherapy. In addition, NNMT has potential as a non-invasive biomarker of cancer in body fluids, including serum (11,12), saliva (13) and urine (14). To the best of our knowledge, the role of NNMT in PCa has not been identified thus far.…”