Abstract
PurposeNicotinamide n‐methyltransferase (NNMT) has good biochemical activity and epigenetic regulation, and has been reported as a major metabolic regulator of cancer. The goal of this study was to investigate the significance of stromal NNMT expression in colorectal cancer (CRC).Patients and methodsStromal expression of NNMT in primary CRC, metastasis CRC, and their non‐cancerous tissues from 1088 CRC patients was examined by immunohistochemistry. The associations between stromal NNMT expression and survival outcomes in 967 patients with stage I‐III CRC were further evaluated with Kaplan‐Meier curve and Cox model analyses.ResultsNNMT expression was mainly sourced from stromal compartments and also elevated in CRC. Patients with high stromal NNMT (IHC‐score ≥ 106) have a worse survival than those patients with low stromal NNMT. In multiple Cox analyses, high expression of stromal NNMT remained as an independent risk factor in CRC for disease‐free survival with a hazard ratio (HR) of 1.415 (95% confidence interval [CI], 1.015‐1.972) and disease‐specific survival with a HR of 5.004 (95% CI, 2.301‐10.883). In addition, high stromal NNMT expression in CRC also indicates the poor survival outcomes in patients with early stage CRC (stage I and II) and in patients who undergo chemotherapy.ConclusionNNMT is mainly located in CRC stromal compartment. High stromal NNMT expression predicts an unfavorable postoperative prognosis.
Highlights
Nicotinamide N-methyltransferase (NNMT) is a known enzyme that catalyzes the pyridine compounds and N-methylation of nicotinamide.[1,2] NNMT transfers a reactive methyl group of S-adenosyl methionine (SAM) to nicotinamide to form the metabolically inert product 1-methyl nicotinamide (1-MNA) and S-adenosyl homocysteine (SAH).[2]
In our coexpression analysis of the genes, the results showed that the expression of NNMT mRNA was highly positively correlated with several known markers of cancer-associated fibroblasts (CAF), such as ACTA2, VIM, TAGLN, FAP, and POSTN
In patient-derived xenografts (PDXs), human stromal cells are replaced by mouse cells, allowing the differentiation of cancer and stromal cell gene expression based on the source of the transcript.[22]
Summary
Nicotinamide N-methyltransferase (NNMT) is a known enzyme that catalyzes the pyridine compounds and N-methylation of nicotinamide.[1,2] NNMT transfers a reactive methyl group of S-adenosyl methionine (SAM) to nicotinamide to form the metabolically inert product 1-methyl nicotinamide (1-MNA) and S-adenosyl homocysteine (SAH).[2]. NNMT mediates SAM depletion and attenuating histone methylation in various cells, including cancer cells,[4] which resulted in the extensive gene expression changes in the tumor stroma. The association between NNMT expression and clinical features and patient survival was analyzed. We found that high expression of stromal NNMT was significantly associated with advanced TNM stages, poor prognosis, and chemotherapy resistance in patients with CRC. The evidence above indicated that stromal NNMT may serve as a promising prognostic biomarker in CRC
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