Updated Functional Roles of NAMPT in Carcinogenesis and Therapeutic Niches

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is notable for its regulatory roles in tumor development and progression. Emerging evidence regarding NAMPT somatic mutations in cancer patients, NAMPT expressional signatures in normal tissues and cancers, and the prognostic significance of NAMPT in many cancer types has attracted attention, and NAMPT is considered a potential biomarker of cancer. Recent discoveries have demonstrated the indirect association and direct biological functions of NAMPT in modulating cancer metastasis, proliferation, angiogenesis, cancer stemness, and chemoresistance to anticancer drugs. These findings warrant further investigation of the underlying mechanisms to provide knowledge for developing novel cancer therapeutics. In this review article, we explore recent research developments involving the oncogenic activities of NAMPT by summarizing current knowledge regarding NAMPT somatic mutations, clinical trials, transcriptome data, and clinical information and discoveries related to the NAMPT-induced signaling pathway in modulating hallmarks of cancer. Furthermore, the comprehensive representation of NAMPT RNA expression in a pancancer panel as well as in specific normal cell types at single-cell level are demonstrated. The results suggest potential sites and cell types that could facilitate NAMPT-related tumorigenesis. With this review, we aim to shed light on the regulatory roles of NAMPT in tumor development and progression, and provide information to guide future research directions in this field.

Keywords: NAMPT; cancer progression; prognosis.

Figure 1

Isoform view of human NAMPT. The position of the stop codon and start site of transcription are indicated by red and green arrowheads, respectively. The matched NAPRTase protein domain in each isoform is marked in orange. The data were retrieved from Ensembl and analyzed.

Figure 2

A pancancer study of whole genomes revealing types and sites of NAMPT gene mutations. Mutation diagram circles are highlighted by colors with respect to the specific mutation types. Light green indicates missense mutations (unknown significance). Gray indicates truncating mutations (putative driver), including frameshift deletion, nonsense, nonstop, and frameshift insertion mutations.

Figure 3

Human NAMPT expression in single cells of different cell types. The NAMPT level was detected by scRNA-seq in various tissues. The RNA expression levels in the cell type clusters were identified in each tissue and visualized by using the UMAP plot of single cells.

Figure 4

NAMPT RNA levels were measured by scRNA-seq in 192 specific cell type clusters, and the relative expression levels are presented. nTPM: TPM values of all samples were normalized separately using the trimmed mean of M values (TMM) to allow for between-sample comparisons and normalized transcript expression values.

Figure 5

NAMPT RNA-seq data for 17 cancer types from TCGA were analyzed and reported as the median number of fragments per kilobase of exon per million reads (FPKM). Normal distribution across the dataset is represented by box plots, shown as the median, 25^th, and 75th percentiles. The points represented the data of outliers if the expression levels are below or above 1.5 times the interquartile range. The data for the analyses were retrieved from HPA database (https://www.proteinatlas.org/, accessed on 28 February 2022).

Figure 6

The representative scheme of NAMPT’s modulations to hallmarks of cancer.