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Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma

Background: Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) to generate 1-methyl nicotinamide (MNAM). Although previous studies have shown that NNMT is frequently dysregulated to promote the onset and progression of many malignancies...

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Autores principales: Zhang, Weixian, Jing, Yue, Wang, Shuai, Wu, Yan, Sun, Yawei, Zhuang, Jia, Huang, Xiaofeng, Chen, Sheng, Zhang, Xiaoxin, Song, Yuxian, Hu, Qingang, Ni, Yanhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599733/
https://www.ncbi.nlm.nih.gov/pubmed/36291696
http://dx.doi.org/10.3390/biom12101487
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author Zhang, Weixian
Jing, Yue
Wang, Shuai
Wu, Yan
Sun, Yawei
Zhuang, Jia
Huang, Xiaofeng
Chen, Sheng
Zhang, Xiaoxin
Song, Yuxian
Hu, Qingang
Ni, Yanhong
author_facet Zhang, Weixian
Jing, Yue
Wang, Shuai
Wu, Yan
Sun, Yawei
Zhuang, Jia
Huang, Xiaofeng
Chen, Sheng
Zhang, Xiaoxin
Song, Yuxian
Hu, Qingang
Ni, Yanhong
author_sort Zhang, Weixian
collection PubMed
description Background: Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) to generate 1-methyl nicotinamide (MNAM). Although previous studies have shown that NNMT is frequently dysregulated to promote the onset and progression of many malignancies, its expression profile, prognostic value and function in oral squamous cell carcinoma (OSCC) are still unknown. Methods: We used untargeted metabolomics based on mass spectrometry to analyze potential metabolite differences between tumors and matched adjacent normal tissues in 40 OSCC patients. Immunohistochemistry (IHC) was used to analyze the NNMT expression profile in OSCC, and the diagnostic and prognostic values of NNMT were evaluated. Next, qPCR and Western blot were used to compare the expression of NNMT in five OSCC cell lines. Stable transfected cell lines were constructed, and functional experiments were carried out to elucidate the effects of NNMT on the proliferation and migration of OSCC cells. Finally, gene set enrichment analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) data to investigate the potential functional mechanisms of NNMT in OSCC. Results: We found that the nicotinamide metabolic pathway was abnormally activated in OSCC tumor tissues compared with normal tissues. NNMT was expressed ubiquitously in tumor cells (TCs) and fibroblast-like cells (FLCs) but was absent in tumor-infiltrating lymphocytes (TILs). OSCC patients with highly expressed NNMT in TCs had higher risk of lymph node metastasis and showed a worse pattern of invasion (POI). Moreover, patients with highly expressed NNMT were also susceptible to postoperative recurrence. Highly expressed NNMT can independently predict shorter disease-free survival and recurrence-free survival. Functionally, we demonstrated that the ectopic expression of NNMT promoted OSCC tumor cell proliferation and migration in vitro. Conversely, silencing exerted significantly opposite effects in vitro. In addition, GSEA showed that highly expressed NNMT was mainly enriched in the epithelial–mesenchymal transformation (EMT) pathway, which displayed a significant positive correlation with the six classic EMT markers. Conclusions: Our study uncovered that NNMT may be a critical regulator of EMT in OSCC and may serve as a prognostic biomarker for OSCC patients. These findings might provide novel insights for future research in NNMT-targeted OSCC metastasis and recurrence therapy.
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spelling pubmed-95997332022-10-27 Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma Zhang, Weixian Jing, Yue Wang, Shuai Wu, Yan Sun, Yawei Zhuang, Jia Huang, Xiaofeng Chen, Sheng Zhang, Xiaoxin Song, Yuxian Hu, Qingang Ni, Yanhong Biomolecules Article Background: Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) to generate 1-methyl nicotinamide (MNAM). Although previous studies have shown that NNMT is frequently dysregulated to promote the onset and progression of many malignancies, its expression profile, prognostic value and function in oral squamous cell carcinoma (OSCC) are still unknown. Methods: We used untargeted metabolomics based on mass spectrometry to analyze potential metabolite differences between tumors and matched adjacent normal tissues in 40 OSCC patients. Immunohistochemistry (IHC) was used to analyze the NNMT expression profile in OSCC, and the diagnostic and prognostic values of NNMT were evaluated. Next, qPCR and Western blot were used to compare the expression of NNMT in five OSCC cell lines. Stable transfected cell lines were constructed, and functional experiments were carried out to elucidate the effects of NNMT on the proliferation and migration of OSCC cells. Finally, gene set enrichment analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) data to investigate the potential functional mechanisms of NNMT in OSCC. Results: We found that the nicotinamide metabolic pathway was abnormally activated in OSCC tumor tissues compared with normal tissues. NNMT was expressed ubiquitously in tumor cells (TCs) and fibroblast-like cells (FLCs) but was absent in tumor-infiltrating lymphocytes (TILs). OSCC patients with highly expressed NNMT in TCs had higher risk of lymph node metastasis and showed a worse pattern of invasion (POI). Moreover, patients with highly expressed NNMT were also susceptible to postoperative recurrence. Highly expressed NNMT can independently predict shorter disease-free survival and recurrence-free survival. Functionally, we demonstrated that the ectopic expression of NNMT promoted OSCC tumor cell proliferation and migration in vitro. Conversely, silencing exerted significantly opposite effects in vitro. In addition, GSEA showed that highly expressed NNMT was mainly enriched in the epithelial–mesenchymal transformation (EMT) pathway, which displayed a significant positive correlation with the six classic EMT markers. Conclusions: Our study uncovered that NNMT may be a critical regulator of EMT in OSCC and may serve as a prognostic biomarker for OSCC patients. These findings might provide novel insights for future research in NNMT-targeted OSCC metastasis and recurrence therapy. MDPI 2022-10-15 /pmc/articles/PMC9599733/ /pubmed/36291696 http://dx.doi.org/10.3390/biom12101487 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Weixian
Jing, Yue
Wang, Shuai
Wu, Yan
Sun, Yawei
Zhuang, Jia
Huang, Xiaofeng
Chen, Sheng
Zhang, Xiaoxin
Song, Yuxian
Hu, Qingang
Ni, Yanhong
Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma
title Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma
title_full Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma
title_fullStr Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma
title_full_unstemmed Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma
title_short Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma
title_sort identification of biological functions and prognostic value of nnmt in oral squamous cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599733/
https://www.ncbi.nlm.nih.gov/pubmed/36291696
http://dx.doi.org/10.3390/biom12101487
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