Nicotinamide N‑methyltransferase induces the proliferation and invasion of squamous cell carcinoma cells

Hah, Young‐Sool; Cho, Hee Young; Jo, Sun Young; Park, Sung Chul; Heo, Eun Phil; Yoon, Tae‐Jin

doi:10.3892/or.2019.7315

Cited by 17 publications

(14 citation statements)

References 32 publications

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“…3B). Our results are consistent with the reports derived from squamous cell carcinoma cells [37], esophageal squamous cell carcinoma cells [19], hepatocellular carcinoma cells [21], gastric cancer cells [15,16], which strongly suggests that the cellular enzyme NNMT serves a crucial role in the migration and invasion of cancer cells.…”

Section: Discussionsupporting

confidence: 93%

Overexpression of Nicotinamide N-methyltransferase mainly covers stroma of colorectal cancer and correlates with unfavorable survival by its product 1-MNA

et al. 2021

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Background: Accumulating evidence indicates that Nicotinamide N-methyltransferase (NNMT) is abnormally expressed in tumor tissues of several cancers including colorectal cancer (CRC) and associated with cancer progression. However, the distribution characteristics and the clinical value of each part of NNMT expression in CRC are still not fully understood. The purpose of this study is to determine the distribution of NNMT expression and its association with survival in CRC. Methods: By using the cancer genome atlas (TCGA) and clinical proteomic tumor analysis consortium (CPTAC), we firstly analyzed the difference of gene and protein levels of NNMT between CRC and normal colorectal tissue. Then, NNMT protein expressions were detected in 18 intraepithelial neoplastic samples and 177 CRC tumor samples through immunohistochemistry in our study cohort. Furthermore, the relationship between NNMT expression and clinicopathological characteristics, overall survival (OS) and disease-free survival (DFS) of CRC patients were analyzed by Pearson χ2 test and log-rank test, respectively, in public datasets and our study cohort. Lastly, the function of NNMT and its product 1-methyl-nicotinamide (1-MNA) on migration and invasion in colorectal cancer cells was analyzed by wound healing assay and transwell assay. Results: We determined that higher NNMT expression in CRC tissues than normal tissues in both gene and protein level in TCGA and CPTAC datasets (all p < 0.05). In addition, the strong relationships of NNMT expression with stromal cells were found in the TCGA cohort. Fortunately, our cohort could validate that the expression of NNMT in tumor stroma cell was significantly higher than that in tumor cell (p < 0.0001), and both of them were significantly higher than that in adjacent normal tissue (ANT) (p < 0.0001 and p < 0.0001, respectively). Furthermore, the positive NNMT expression in tumor cell and stromal cell were associated with series of unfavorable clinical characteristics, including advanced TNM stage, lymph node metastasis, distant metastasis (all p < 0.05). Also, higher NNMT was associated with unfavorable survival both in our study and public datasets, including TCGA and two Gene Expression Omnibus (GEO) datasets (GSE33113 and GSE17538). Moreover, the functional experiments showed that stromal cells with high NNMT expression can secret 1-MAN to promote migration and invasion of CRC cells in vitro. Conclusions: In CRC, NNMT is overexpressed in tumor cells and stroma cells, and then mainly expressed in tumor stroma cells. Overexpression of NNMT in tumor cell and stroma cell both are associated with metastasis and unfavorable survival. Besides, stromal cells with high NNMT expression secrets 1-MAN to promote migration and invasion of CRC cells. Therefore, NNMT may be a potential prognostic indicator in CRC patients.

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Section: Discussionsupporting

confidence: 93%

Overexpression of Nicotinamide N-methyltransferase mainly covers stroma of colorectal cancer and correlates with unfavorable survival by its product 1-MNA

et al. 2021

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“…Decreased histone methylation then regulated signaling pathways associated with acquisition of a more aggressive phenotype. Consistently, NNMT knockdown decreased expression of EMT-related genes MMP9, SNAI2, vimentin, WNT5B, ZEB1/2; and suppressed cell invasion and migration in squamous cell carcinoma [37]. Aberrant methylation of DNA/histone driven by SAM thus has contrasting effects on EMT to that induced by demethylation blockade via 2-HG/succinate/ fumarate.…”

Section: Sam/sah Ratiomentioning

confidence: 80%

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

et al. 2020

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Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.

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“…A subsequent study analyzed differences in protein expression between the human skin squamous carcinoma cell lines SCC12 and SCC13, with the aim to identify which genes determine the high invasive potential displayed by the SCC12 cell line compared with the poorly invasive SCC13 cell line [ 93 ].…”

Section: Involvement Of Nnmt In Scmentioning

confidence: 99%

Beyond Nicotinamide Metabolism: Potential Role of Nicotinamide N-Methyltransferase as a Biomarker in Skin Cancers

Campagna

Pozzi

Salvolini

et al. 2021

Cancers

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Skin cancers (SC) collectively represent the most common type of malignancy in white populations. SC includes two main forms: malignant melanoma and non-melanoma skin cancer (NMSC). NMSC includes different subtypes, namely, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Merkel cell carcinoma (MCC), and keratoacanthoma (KA), together with the two pre-neoplastic conditions Bowen disease (BD) and actinic keratosis (AK). Both malignant melanoma and NMSC are showing an increasing incidence rate worldwide, thus representing an important challenge for health care systems, also because, with some exceptions, SC are generally characterized by an aggressive behavior and are often diagnosed late. Thus, identifying new biomarkers suitable for diagnosis, as well as for prognosis and targeted therapy is mandatory. Nicotinamide N-methyltransferase (NNMT) is an enzyme that is emerging as a crucial player in the progression of several malignancies, while its substrate, nicotinamide, is known to exert chemopreventive effects. Since there is increasing evidence regarding the involvement of this enzyme in the malignant behavior of SC, the current review aims to summarize the state of the art as concerns NNMT role in SC and to support future studies focused on exploring the diagnostic and prognostic potential of NNMT in skin malignancies and its suitability for targeted therapy.

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Nicotinamide N‑methyltransferase induces the proliferation and invasion of squamous cell carcinoma cells

Cited by 17 publications

References 32 publications

Overexpression of Nicotinamide N-methyltransferase mainly covers stroma of colorectal cancer and correlates with unfavorable survival by its product 1-MNA

Overexpression of Nicotinamide N-methyltransferase mainly covers stroma of colorectal cancer and correlates with unfavorable survival by its product 1-MNA

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

Beyond Nicotinamide Metabolism: Potential Role of Nicotinamide N-Methyltransferase as a Biomarker in Skin Cancers

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