NAD+ associated genes as potential biomarkers for predicting the prognosis of gastric cancer.

ABSTRACT

Nicotinamide adenine dinucleotide (NAD+) plays an essential role in cellular metabolism, mitochondrial homeostasis, inflammation, and senescence. However, the role of NAD+-regulated genes, including coding and long non-coding genes in cancer development is poorly understood. We constructed a prediction model based on the expression level of NAD+ metabolism-related genes (NMRGs). Furthermore, we validated the expression of NMRGs in gastric cancer (GC) tissues and cell lines; additionally, ß-nicotinamide mononucleotide (NMN), a precursor of NAD+, was used to treat the GC cell lines to analyze its effects on the expression level of NMRGs lncRNAs and cellular proliferation, cell cycle, apoptosis, and senescence-associated secretory phenotype (SASP). A total of 13 NMRGs-related lncRNAs were selected to construct prognostic risk signatures, and patients with high-risk scores had a poor prognosis. Some immune checkpoint genes were upregulated in the high-risk group. In addition, cell cycle, epigenetics, and senescence were significantly downregulated in the high-risk group. Notably, we found that the levels of immune cell infiltration, including CD8 T cells, CD4 naïve T cells, CD4 memory-activated T cells, B memory cells, and naïve B cells, were significantly associated with risk scores. Furthermore, the treatment of NMN showed increased proliferation of AGS and MKN45 cells. In addition, the expression of SASP factors (IL6, IL8, IL10, TGF-ß, and TNF-α) was significantly decreased after NMN treatment. We conclude that the lncRNAs associated with NAD+ metabolism can potentially be used as biomarkers for predicting clinical outcomes of GC patients.