Accumulation of Nicotinamide N-Methyltransferase (NNMT) in Cancer-associated Fibroblasts: A Potential Prognostic and Predictive Biomarker for Gastric Carcinoma

Abstract

Nicotinamide N-methyltransferase (NNMT), a major metabolic regulator, has been identified as a predictor of cancer prognosis in ovarian and colorectal cancers. The study aims to evaluate the significance of stromal NNMT in gastric cancer (GC). Expression of stromal NNMT in 612 GC and 92 non-malignant tissues specimens was investigated by immunohistochemistry (IHC). The association between NNMT expression and occurrence of cancer or patient outcome was further analyzed, and the factors contributing to disease prognosis were evaluated by multiple Cox models. Stromal NNMT expression was higher in the malignant tissue ( p<0.001). NNMT expression was significantly associated with GC stage ( p=0.006). Compared to stromal “NNMT-low” cases, “NNMT-high” cases has lower disease-specific survival (hazard ratio [HR], 2.356; 95% confidence interval [CI] = 1.591–3.488; p<0.001) and disease-free survival (HR = 2.265; 95% CI = 1.529–3.354; p<0.001), as observed by multivariate Cox analysis after adjusting for stromal NNMT expression with other factors such as tumor grade and size. Notably, patients with stage II NNMT-low GC might be negatively affected by adjuvant chemotherapy, but lower stromal NNMT expression predicted a more favorable prognosis for GC. Our study confirmed that stromal NNMT expression is significantly increased in GC, which predicts an unfavorable post-operative prognosis for GC:

Prognostic value of nicotinamide adenine dinucleotide (NAD+) metabolic genes in patients with stomach adenocarcinoma based on bioinformatics analysis

“…Both knockdown and pharmacological inhibition of NNMT have been found to lead to an increase in NAD + content ( 12 ). Previous research showed that NNMT expression was substantially linked with GC stage, and increased stromal NNMT expression predicted poor prognosis in GC, which is consistent with our data ( 36 ). It is worth noting that Liu et al demonstrated that NNMT directly interacts with TTPAL to activate PI3K/AKT signaling to promote gastric carcinogenesis, hence partaking in cancer proliferation, invasion, metastasis and drug resistance ( 37 ).…”

Epigenetic Reprogramming of Tumor-Associated Fibroblasts in Lung Cancer: Therapeutic Opportunities

“…Moreover, it was reported that NNMT expression was necessary and sufficient to elicit a tumor-promoting phenotype in TAFs in vitro and in vivo, revealing that histone methylation has a major role in shaping such a pro-malignant phenotype, and supporting that NNMT or other aberrant methyltransferase activities in TAFs could be a therapeutically interesting target to normalize the tumor stroma [37]. In agreement with this interpretation, NNMT was upregulated in TAFs in gastric and colorectal cancer [39], and is associated with poor prognosis in several solid tumors including NSCLC. Moreover, NNMT overexpression was linked with the expression of PD-L1 and other immune checkpoint markers [38,40], whereas NNMT silencing was associated with decreased tumorigenicity in NSCLC [41].…”

Drug metabolism‐related eight‐gene signature can predict the prognosis of gastric adenocarcinoma

“…As for NNMT , related studies found that high NNMT expression in stromal cells may predict an unfavorable postoperative prognosis for gastric carcinoma. 35 NNMT is known to act as a negative predictor for gastric carcinoma prognosis and is correlated with immune infiltrates 36 , 37 . These findings confirmed our results, and upregulated NNMT in gastric cancer cells may promote the occurrence of epithelial‐mesenchymal transition by activating TGF‐β1/SMAD signaling, 38 thereby leading to tumor recurrence and metastasis.…”