Nicotinamide N-methyltransferase overexpression is associated with Akt phosphorylation and indicates worse prognosis in patients with nasopharyngeal carcinoma

Abstract

Nicotinamide N-methyltransferase (NNMT) is overexpressed in many human cancers and is associated with poor prognosis. Akt (also known as protein kinase B) is an evolutionarily conserved serine/threonine kinase, serving as a downstream effector of the phosphatidylinositol 3-kinase signaling pathway. NNMT was first identified as a differentially upregulated gene in nasopharyngeal cancer tissues through data mining from published transcriptomic databases. Since no prior study has attempted to evaluate the clinical significance of NNMT or phosphorylated Akt (pAkt) expression in nasopharyngeal cancer, this study explores their expression in a large cohort of patients with nasopharyngeal cancer. The study included 124 nasopharyngeal cancer patients who were free of distant metastasis at initial diagnosis. Pathological slides were reviewed and clinical findings collected. We evaluated the expression of NNMT and pAkt immunohistochemically, stratified them into two groups (high and low expression) and examined the correlation with disease-specific survival (DSS), metastasis-free survival (MeFS), local recurrence-free survival (LRFS), and various clinicopathological factors. NNMT expression was significantly positively associated with pAkt expression. The high expression of both markers was significantly associated with an increment of tumor stage (p = 0.006 and p = 0.006, respectively). High expression of NNMT correlated significantly with a more aggressive clinical course and a significantly shorter DSS. Furthermore, NNMT expression and pAkt expression were strongly predictive of MeFS (p = 0.008; p = 0.0063) and LRFS (p = 0.005; p = 0.0125). In multivariate analysis, high expression of NNMT remained as a robust prognosticator for both end points evaluated. It independently portended inferior DSS (p = 0.02, HR = 1.976) and worse MeFS (p = 0.029, HR = 2.022) after tumor stage (p = 0.033, HR = 2.150; p = 0.028, HR = 2.942, for DSS and LRFS, respectively). We found NNMT positively correlated with pAkt expression and was independent adverse prognosticators of patient survival. NNMT therefore has potential utility as an indicator for prognosis, predicting treatment response to chemotherapy or radiation therapy, and even as a therapeutic target in the future.

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].…”

“…Several recent studies have shown that Akt signaling pathway may be linked with NNMT deregulation in cancer. Win et al [17] observed that NNMT overexpression was positively correlated with Akt phosphorylation and implied worse prognosis in patients with nasopharyngeal carcinoma. Thomas et al [24] found NNMT expression regulated neuron morphology in vitro via the sequential activation of the EFNB2 and Akt cellular signaling pathways.…”

“…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.…”

Prognostic Significance of the EGFR Pathway in Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis

“…A systematic literature search was performed which showed that patients with NPC with higher AKT expression had a worse prognosis, which was previously highlighted by a review by Chen et al [30]. If this association is because higher stage tumors express more AKT is not clear, because the patients in these studies were not stratified for tumor stage [22,24]. Patient populations in these studies however did not show a dominance of a higher or lower stage of disease.…”

“…The HR of Kim et al [23] was extracted directly from the article. [24] there is also a correlation between an increased AKT expression and lymph node and distant metastasis. No other significant effect for TNM stage was observed (see Table 1: AKT, PI3CA, mTOR and PTEN).…”