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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MDPI AG
2022-10-01
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| Online Access: | https://www.mdpi.com/2218-273X/12/10/1487 |
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| author | Weixian Zhang Yue Jing Shuai Wang Yan Wu Yawei Sun Jia Zhuang Xiaofeng Huang Sheng Chen Xiaoxin Zhang Yuxian Song Qingang Hu Yanhong Ni |
| author_facet | Weixian Zhang Yue Jing Shuai Wang Yan Wu Yawei Sun Jia Zhuang Xiaofeng Huang Sheng Chen Xiaoxin Zhang Yuxian Song Qingang Hu Yanhong Ni |
| author_sort | Weixian Zhang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T20:37:02Z |
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| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T20:37:02Z |
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| spelling | doaj.art-8274931f6bc943628dad4348e6df55282023-11-23T23:09:26ZengMDPI AGBiomolecules2218-273X2022-10-011210148710.3390/biom12101487Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell CarcinomaWeixian Zhang0Yue Jing1Shuai Wang2Yan Wu3Yawei Sun4Jia Zhuang5Xiaofeng Huang6Sheng Chen7Xiaoxin Zhang8Yuxian Song9Qingang Hu10Yanhong Ni11Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaDepartment of Oral Pathology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaDepartment of Oral Pathology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaDepartment of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaCentral Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, ChinaBackground: 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.https://www.mdpi.com/2218-273X/12/10/1487Nicotinamide N-methyltransferaseoral squamous cell carcinomaprognosismetabolomicsnicotinamideepithelial–mesenchymal transformation |
| spellingShingle | Weixian Zhang Yue Jing Shuai Wang Yan Wu Yawei Sun Jia Zhuang Xiaofeng Huang Sheng Chen Xiaoxin Zhang Yuxian Song Qingang Hu Yanhong Ni Identification of Biological Functions and Prognostic Value of NNMT in Oral Squamous Cell Carcinoma Biomolecules Nicotinamide N-methyltransferase oral squamous cell carcinoma prognosis metabolomics nicotinamide epithelial–mesenchymal transformation |
| 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 | Nicotinamide N-methyltransferase oral squamous cell carcinoma prognosis metabolomics nicotinamide epithelial–mesenchymal transformation |
| url | https://www.mdpi.com/2218-273X/12/10/1487 |
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