Abstract
BackgroundThe role of nicotinamide N-methyltransferase (NNMT) in ovarian cancer is still elusive. Our aim is to explore the expression of NNMT in ovarian cancer and to assess its association with patient prognosis and treatment response.MethodsWe first analyzed the differential expression of NNMT among fallopian tube epithelium, primary ovarian cancers, metastatic ovarian cancers, and recurrent ovarian cancers using Gene Expression Ominus (GEO) database (GSE10971, GSE30587, GSE44104 and TCGA datasets). Then, we assessed the association of NNMT expression with clinical and molecular parameters using CSIOVDB database and GSE28739 dataset. Next, we evaluate the association of NNMT expression with the prognosis of ovarian cancer patients in both GSE9891 dataset and TCGA dataset. Finally, GSE140082 dataset was used to explore the association of NNMT expression with bevacizumab response.ResultsNNMT expression was significantly elevated in lymphovascular space invasion (LVSI)-positive ovarian cancers compared with that in LVSI-negative ovarian cancers (TCGA dataset, P < 0.05), Moreover, increased expression of NNMT was associated with increased tumor stage, grade, and mesenchymal molecular subtype (CSIOVDB database). Survival analysis indicated that increased expression of NNMT was associated with a reduced OS in both GSE9891 dataset (HR: 2.28, 95%CI: 1.51–3.43, Log-rank P < 0.001) and TCGA dataset (HR: 1.55, 95%CI: 1.02–2.36, Log-rank P = 0.039). Multivariate analysis further confirmed the negative impact of NNMT expression on OS in ovarian cancer patients in those two datasets. Furthermore, the NNMT-related nomogram showed that NNMT shared a larger contribution to OS, compared with debulking status. More interestingly, bevacizumab conferred significant improvements in OS for patients with low NNMT expression (HR: 0.56, 95%CI: 0.31–0.99, Log-rank P = 0.049). In contrast, patients with high NNMT expression didn’t benefit from bevacizumab treatment significantly (HR: 0.85, 95%CI: 0.48–1.49, Log-rank P = 0.561). NNMT expression was positively correlated with the expression of genes, LDHA and PGAM1, involved in Warburg effect.ConclusionsIn conclusion, NNMT expression is associated with the aggressive behavior of ovarian cancer, correlates with a poor prognosis, and is predictive of sensitivity to bevacizumab treatment.
Highlights
The role of nicotinamide N-methyltransferase (NNMT) in ovarian cancer is still elusive
In conclusion, NNMT expression is associated with the aggressive behavior of ovarian cancer, correlates with a poor prognosis, and is predictive of sensitivity to bevacizumab treatment
When using limma R package, the Benjamini-Hochberg multiple comparison adjustment was applied and the adjusted P value < 0.05 was Differential expression of NNMT in fallopian tube epithelium (FTE), primary ovarian cancers (POCs)/primary tubal cancers (PTCs), metastatic ovarian cancers (MOCs), and recurrent ovarian cancers (ROCs) The mean expression value of NNMT was elevated in POCs/PTCs compared with that in FTs (Fig. 1a, GSE10971), and was increased in MOCs and ROCs compared with POCs (Fig. 1b, GSE30587; Fig. 1c, GSE44104)
Summary
The role of nicotinamide N-methyltransferase (NNMT) in ovarian cancer is still elusive. Our aim is to explore the expression of NNMT in ovarian cancer and to assess its association with patient prognosis and treatment response. After debulking surgery and combined chemotherapy, most of the patients relapse and die from drug resistance. This underscores the significant clinical need to decipher the molecular biology of ovarian cancer and to identify new biomarkers to predict prognosis, which may be translated into personalized treatment strategies and survival improvements. Nicotinamide N-methyltransferase (NNMT) is an Sadenosylmethionine-dependent enzyme, which plays a critical role in the biotransformation and detoxification of many drugs and xenobiotic compounds [2]. Its role in ovarian cancer is still largely elusive [12, 13]
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