Identification of Nicotinamide N-Methyltransferase as a Novel Tumor Marker for Renal Clear Cell Carcinoma

Sartini, Davide; Muzzonigro, Giovanni; Milanese, Giulio; Pierella, Francesca; Rossi, Valentina; Emanuelli, Monica

doi:10.1016/j.juro.2006.07.046

Cited by 70 publications

(88 citation statements)

References 20 publications

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“…Recent studies have demonstrated that NNMT is aberrantly expressed in a number of tumors, suggesting that NNMT serves an important function in tumor development (12,13). Additionally, the serum levels of NNMT were significantly increased in patients with colorectal, lung and renal cell carcinoma compared with those in the control group (10,14,15). Previous studies have also demonstrated that the upregulation of NNMT is associated with poor prognosis, advanced tumor stage, tumor cell migration and invasion (9,16,17).…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression

et al. 2018

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Abstract. Previous studies have demonstrated that nicotinamide N-methyltransferase (NNMT) is aberrantly expressed in a number of tumors. In the present study, it was demonstrated that the gene and protein levels of NNMT were significantly increased in gastric cancer cells. Furthermore, upregulation of NNMT significantly increased the expression of mesenchymal markers, including α-smooth muscle actin (SMA), vimentin and fibronectin, but decreased the levels of epithelial cadherin. Since transforming growth factor (TGF)-β1 may serve a key function in epithelial-mesenchymal transition (EMT), the effects of NNMT on the expression of TGF-β1 were investigated in BGC-823 cells. The results demonstrated that overexpression of NNMT significantly induced the expression of TGF-β1. However, knockdown of NNMT inhibited the expression of TGF-β1, mothers against decapentaplegic homolog (Smad)2 and α-SMA. Additionally, pre-incubation with TGF-β1 partially eliminated NNMT-mediated changes in EMT. Collectively, the results demonstrated that upregulation of NNMT in gastric cancer cells may increase the expression of TGF-β1, therefore activating TGF-β1/Smad signaling, which in turn promotes EMT.

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Section: Introductionmentioning

confidence: 99%

Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression

et al. 2018

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“…In renal cell carcinoma NNMT mRNA was overexpressed in 100% of clear cell renal cell carcinomas (ccRCCs) compared to adjacent noncancerous tissue. Moreover, NNMT expression level in ccRCC showed an inverse correlation with tumor size, suggesting a role of the enzyme in tumour growth (3). In oral squamous cell carcinoma NNMT upregulation inversely correlated with pT, pathological staging and lymph node metastasis (4).…”

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confidence: 99%

Inhibiting Proliferation in KB Cancer Cells by RNA Interference-Mediated Knockdown of Nicotinamide N-Methyltransferase Expression

Pozzi

Mazzotta²,

Muzio

et al. 2011

Int J Immunopathol Pharmacol

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The enzyme Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide and other pyridines, playing a pivotal role in the biotransformation and detoxification of many drugs and xenobiotic compounds. Several tumours have been associated with abnormal NNMT expression, however its role in tumour development remains largely unknown. In this study we investigated expression levels of Nicotinamide N-methyltransferase in a cancer cell line and we evaluated the effect of shRNA-mediated silencing of NNMT on cell proliferation. Cancer cells were examined for NNMT expression by semiquantitative RT-PCR and Western blot analysis. A HPLC-based catalytic assay was performed to assess enzyme activity. Cells were transfected with four shRNA plasmids against NNMT and control cells were treated with transfection reagent only (mock). The efficiency of gene silencing was detected by Real-Time PCR and Western blot analysis. MTT cell proliferation assay and the soft agar colony formation assay were then applied to investigate the functional changes in cancerous cell. NNMT mRNA was detected in cancer cells, showing a very high expression level. In keeping with the results of RT-PCR analysis, the protein level and NNMT enzyme activity were particularly high in KB cells. ShRNA vectors targeted against NNMT efficiently suppressed gene expression, showing inhibition observed at both the mRNA and protein levels. Down-regulation of NNMT significantly inhibited cell proliferation and decreased colony formation ability on soft agar. The present data support the hypothesis that the enzyme plays a role in tumour expansion and its inhibition could represent a possible molecular approach to the treatment of cancer.Tumour arises as a result of gene mutations and abnormal expression that endow the cell with many specific functional capabilities, such as cell proliferation, invasion and metastasis (l). The cellular and biochemical factors that underline cancer dissemination are poorly understood. Treatment of

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“…Interestingly, many cancers have been reported to have an enhanced expression of NNMT. [22][23][24][25] As NNMT activity is positively related to nicotinamide levels, as demonstrated by Riederer et al, 20 it is likely that elevated NNMT expression in cancers may therefore be related to excessive niacin intake.…”

Section: Discussionmentioning

confidence: 92%

Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives

Sun

Lun

et al. 2011

Hypertens Res

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Nicotinamide and catecholamines are both degraded by S-adenosylmethionine-dependent methylation. Whether excess nicotinamide affects the degradation of catecholamines is unknown. The aim of this study was to investigate the effect of nicotinamide on the methylation status of the body and methylation-mediated catecholamine degradation in both normotensives and hypertensives. The study was conducted in 19 normotensives and 27 hypertensives, using a nicotinamide-loading test (100 mg orally). Plasma nicotinamide, N 1 -methylnicotinamide, homocysteine (Hcy), betaine, norepinephrine, epinephrine, normetanephrine and metanephrine levels before and 5 h after nicotinamide loading were measured. Compared with normotensives, hypertensives had higher baseline (fasting) levels of plasma nicotinamide, Hcy and norepinephrine, but lower levels of plasma normetanephrine, a methylated norepinephrine derivative. Nicotinamide loading induced a significant increase in the levels of plasma N 1 -methylnicotinamide and norepinephrine, and a significant decrease in the levels of O-methylated epinephrine (metanephrine) and betaine, a major methyl donor, in both hypertensives and normotensives. Moreover, nicotinamide-loading significantly increased plasma Hcy levels, but decreased plasma normetanephrine levels in normotensives. The baseline levels of plasma epinephrine in hypertensives were similar to those of normotensives, but the post-nicotinamideloading levels of plasma epinephrine in hypertensives were higher than those of normotensives. This study demonstrated that excess nicotinamide might deplete the labile methyl pool, increase Hcy generation and inhibit catecholamine degradation. It also revealed that hypertensives had an abnormal methylation pattern, characterized by elevated fasting plasma levels of unmethylated substrates, nicotinamide, Hcy and norepinephrine. Therefore, it seems likely that high nicotinamide intake may be involved in the pathogenesis of Hcy-related cardiovascular disease.

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Identification of Nicotinamide N-Methyltransferase as a Novel Tumor Marker for Renal Clear Cell Carcinoma

Abstract: Our results indicate that a marked nicotinamide N-methyltransferase increase is a peculiar feature of clear cell renal cell carcinoma. Additional studies may establish the role of nicotinamide N-methyltransferase in tumor formation and progression.

Cited by 70 publications

References 20 publications

Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression

Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression

Inhibiting Proliferation in KB Cancer Cells by RNA Interference-Mediated Knockdown of Nicotinamide N-Methyltransferase Expression

Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives

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