Expression and Clinical Significance of Nicotinamide N-Methyltransferase in Cervical Squamous Cell Carcinoma

Abstract

Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme, overexpressed in various human malignancies. It is associated with cancer progression and resistance to treatment. The role of NNMT in cervical cancer has not been studied thus far. We aimed to evaluate expression of NNMT in cervical squamous cell carcinoma (SCC) and investigate its clinical significance. NNMT expression was assayed by use of immunohistochemistry in 61 cases of SCC, 11 cases of high-grade squamous intraepithelial lesion, 17 cases of low-grade squamous intraepithelial lesion, and 51 benign cervical tissues. NNMT immunoreactivity was scored based on staining intensity and percentage of positively stained cells. The expression of NNMT was significantly higher in SCC than in benign tissue, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion (P<0.001). NNMT expression in benign tissue was significantly lower than in low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion. When stratified according to stage, NNMT expression was significantly higher in patients with stage III and IV than those in stage I and II disease (P=0.009). For all stages, patients with metastatic pelvic or para-aortic lymph nodes had significantly higher NNMT expression than patients without nodal involvement (P=0.001). Although preliminary, this is the first study to detect overexpression of NNMT in SCC and increased expression associated with advanced stage and metastatic lymph nodes. NNMT should be investigated further in cervical cancer as a potential therapeutic target and a prognostic indicator.

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

“…We have shown that NNMT protects against mitochondrial toxins in S.NNMT.LP cells [37,[119][120][121]. NNMT induces resistance of colorectal cancer cells to 5-fluorouracil (5-FU) [122] and has been implicated in the resistance of cervical squamous cell carcinoma to treatment [123]. Increased expression of NNMT in non-small-cell lung cancer cells results in resistance to EGFR-tyrosine kinase inhibitors [124].…”

“…Taken with the fact that NNMT expression is not required for a basic cancer phenotype [37], it is likely that NNMT plays no role in the initiation of tumorigenesis but instead is recruited as part of an evolution of the tumour phenotype to provide a survival advantage over surrounding non-cancerous cells. This is evidenced by (1) pro-oncogenic changes in epigenetic regulation [59], promotion of the activities of pro-oncogenic NAD+-dependent pathways such as sirtuins and PARP-1 [69,[141][142][143], maintenance of mitochondrial function and support of the Warburg effect [37,97,195], activation of pro-oncogenic signalling pathways such as Akt [107,108] and protection against anti-cancer drugs [37,[119][120][121][122][123][124][125]. We have shown that SH-SY5Y cells expressing NNMT demonstrate reduced cell death in response to toxins compared to wild-type SH-SY5Y which have no endogenous NNMT expression [37,119], and as discussed elsewhere in this review, numerous other studies have demonstrated increased drug resistance in response to increased NNMT expression.…”

Nicotinamide N‐methyltransferase in nonmelanoma skin cancers

“…Kaplan-Meier curves demonstrated that NNMT represents an important negative prognostic predictor of overall survival of gastric cancer patients. 38 In the work by Akar et al 39 , enzyme levels were significantly higher in patients with advanced-stage cervical SCC compared with those diagnosed with early-stage tumours. Furthermore, enzyme expression was positively correlated with the presence of pelvic or para-aortic lymph node metastasis.…”

The Utility of Nicotinamide N-Methyltransferase as a Potential Biomarker to Predict the Oncological Outcomes for Urological Cancers: An Update

“…Significant NNMT upregulation was recently found in epithelial neoplasms [68][69][70][71][72][73] and in association with cancer stem cells (CSCs) [74][75][76][77][78]. Regarding women's cancers, enzyme overexpression was detected in breast [79][80][81], endometrial [82], cervical [83] and ovarian [84] cancer.…”