title: 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.
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, 901 Chunghwa Road, Yung Kang Dist., Tainan County, 710, Taiwan.
authors.forename: Khin Than
authors.initials: KT
authors.lastname: Win
authors.forename: Sung-Wei
authors.initials: SW
authors.lastname: Lee
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Lin
authors.forename: Ching-Yih
authors.initials: CY
authors.lastname: Lin
authors.forename: Chung-Hsi
authors.initials: CH
authors.lastname: Hsing
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D059248:Chemoradiotherapy; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009367:Neoplasm Staging; D050903:Nicotinamide N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D050903:Nicotinamide N-Methyltransferase; D051057:Proto-Oncogene Proteins c-akt