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Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma.

ABSTRACT: Grade 1 (G1) endometrioid carcinoma (EC) is relatively a good prognosis. However, in a minority of cases, G1 shows an aggressive histological pattern known as the microcystic, elongated, and fragmented (MELF) pattern. We previously reported that EC with high expression levels of S100A4 and serum deprivation-response protein (SDPR) was related to MELF pattern invasion. However, the molecular features of the invasive front area of the MELF pattern have not been investigated. In this study, we searched for genes preferentially expressed in the invasive front area of EC with the MELF pattern using laser microdissection and RNA sequencing, and showed that nicotinamide N-methyltransferase (NNMT) is related to MELF pattern invasiveness. Immunohistochemical analyses confirmed high NNMT expression in the invasive front area of the MELF pattern. Moreover, NNMT promoted migration, invasion, colony formation, epithelial-mesenchymal transition (EMT), and chemoresistance using EC cell lines. We speculate that depletion of NNMT promotes histone methylation and leads to tumor suppression because NNMT consumes S-adenosyl methionine (SAM), which is an essential methylation cofactor. NNMT knockout cells showed enhanced expression of H3K9me2. RNA sequencing using NNMT knockout cell lines suggested that methylation of H3K9 leads to repression of the transcription of various oncogenic genes. Our findings demonstrate the possibility that NNMT inhibitors, which are expected to be used for the treatment of metabolic disorders, would be effective for the treatment of aggressive EC. This is the first report of gene analyses focusing on the morphological changes associated with MELF pattern invasion of EC.

SUBMITTER: Tahara S

PROVIDER: S-EPMC8633241 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-10-18 | GSE171034 | GEO

Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma [RNA-seq]

Project description:In endometrioid carcinoma (EC), grade 1 (G1) EC is generally associated with a good prognosis. However, in a minority of G1, we often find a more aggressive histological pattern: MELF (microcystic, elongated, and fragmented) pattern. We previously revealed that EC with high expression of S100A4 and serum deprivation-response protein (SDPR) was related to MELF pattern invasion. However, the molecular feature of the invasive front area of MELF pattern has not been investigated. In the current study, we searched for genes preferentially expressed in the invasive front area of EC with MELF pattern by using laser microdissection and RNA sequencing, and revealed that Nicotinamide N-methyltransferase (NNMT) is related to invasiveness of MELF pattern. We confirmed that NNMT expression was high in the invasive front area of MELF pattern in immunohistochemical analysis. Moreover, using endometrioid carcinoma cell lines, we showed that NNMT promotes migration, invasion, colony formation, epithelial-mesenchymal transition (EMT), and chemoresistance. We speculated that depletion of NNMT promotes histone methylation and leads to tumor suppression because NNMT consumes S-adenosyl methionine (SAM), which is an essential methylation cofactor. We showed that NNMT-knockout cells the expression of H3K9me2 was enhanced. We speculate that methylation of H3K9 lead to repress the transcription of various oncogenic genes by performing RNA sequencing using NNMT-knockout cell lines. Our findings showed the possibility that NNMT inhibitors, which are expected to be used for the treatment of metabolic disorders, is effective for the treatment of an aggressive EC. This is the first report of the gene analysis focused on the morphological changes of MELF pattern invasion of EC.

2021-10-18 | GSE171032 | GEO

Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma [RNA-seq_pico input]

2021-10-18 | GSE171033 | GEO

Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

Project description:Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

| PRJNA718189 | ENA

Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma [RNA-seq]

Project description:Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma [RNA-seq]

| PRJNA718191 | ENA

Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma [RNA-seq_pico input]

Project description:Nicotinamide N-methyltransferase is related to MELF pattern invasion in endometrioid carcinoma [RNA-seq_pico input]

| PRJNA718192 | ENA

S100A4 accelerates the proliferation and invasion of endometrioid carcinoma and is associated with the "MELF" pattern.

Project description:Endometrioid carcinoma (EC) is one of the most common malignancies of the female genital system. Although the behavior of EC ranges from an excellent prognosis to aggressive disease with a poor outcome, the factors that determine its diversity have not been determined. Here, we show that S100A4, a calcium-binding protein of the EF-hand type, is correlated with the proliferation and invasion ability of EC. We demonstrated previously that EC cells with high aldehyde dehydrogenase (ALDH) activity were more tumorigenic than ALDH-lo cells. Screening by shotgun proteomics demonstrated that the expression level of S100A4 in ALDH-hi EC cells was significantly higher than that in ALDH-lo cells. S100A4-knockout cells generated by the CRISPR/Cas9 system showed reduced proliferation and invasion. These cells showed impaired AKT phosphorylation and matrix metalloproteinase-2 activation, accounting for their impaired proliferation and invasion, respectively. Furthermore, in clinical EC samples, elevated expression of S100A4 was highly related to myometrial and lymphatic invasion in well to moderately differentiated EC. Notably, strong and diffuse expression of S100A4 was observed in tumor tissues with a microcystic, elongated and fragmented ("MELF") pattern, which is associated with a highly invasive EC phenotype. Collectively, our results demonstrate not only that high expression of S100A4 contributes to an aggressive phenotype of EC, but also that its elevated expression is closely related to the MELF histopathological pattern.

| S-EPMC5021035 | biostudies-literature

Tumor-Associated T-Lymphocytes and Macrophages are Decreased in Endometrioid Endometrial Carcinoma with MELF-Pattern Stromal Changes.

Project description:Microcystic, elongated, fragmented (MELF)-pattern is an unusual morphology of myometrial invasive front in endometrioid endometrial carcinoma (EA). The aim of the study was to investigate potential correlation between MELF-pattern and peritumoral inflammatory immune response. A total of 96 out of 368 patients were included in this study. CD3, CD20, CD57. CD68 and S100 markers were used for the detection of tumor-associated T-lymphocytes (TAT), tumor-associated B-lymphocytes (TAB), tumor-associated NK-lymphocytes (NK), tumor-associated macrophages and dendritic cells respectively. Mann-Whitney tests, receiver operating characteristic (ROC) curve analysis, and Spearman correlation were used as methods for statistical analyses. Odds ratio with 95% confidence interval (95% CI) was determined with the use of a logistic regression model. A p?<?0.05 was considered statistically significant. Our results suggested that the number of CD3 and CD68 cells were significantly lower (p?<?0.001) in cases of endometrioid carcinoma with MELF-pattern. A significant correlation between the presence of MELF-pattern and decrease of CD3 positive T-lymphocytes (r?=?0.691; p?<?0.001) was also observed. Additionally, we found an inverse correlation between the presence of MELF-pattern and TAM (r?=?0.568; p?=?0.001). Therefore, our data suggest that MELF-pattern may be associated with EA stroma fibrosis that contains immune cells infiltration and demonstrated a decrease in the number of TAT and TAM cells. This may indicate the poor clinical prognosis of this disease.

| S-EPMC6250614 | biostudies-literature

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

Project description:Cutaneous squamous cell carcinoma (cSCC) is a common malignancy initiated by keratinocytes of the epidermis, which are able to invade the dermis and its periphery. Although most patients with cSCC present with curable localized tumors, recurrence, metastasis and mortality occasionally occur. In the present study, nicotinamide N?methyltransferase (NNMT) was identified as an upregulated protein in the SCC12 cell line, which has high invasive potential compared with the SCC13 cell line. The effects of NNMT knockdown on proliferation, migration and invasion were investigated using SCC cells. shRNA?mediated downregulation of NNMT expression levels inhibited the proliferation and density?dependent growth of SCC12 cells. In addition, the results of a cell motility assay showed that the migration and invasion of SCC cells were markedly decreased in NNMT?knockdown cells. The assessment of epithelial?mesenchymal transition (EMT)?associated gene expression using PCR array analysis revealed that high NNMT expression levels were accompanied by high expression levels of EMT?associated genes, and that NNMT knockdown effectively suppressed the expression of matrix metalloproteinase 9, osteopontin, versican core protein and zinc finger protein SNAI2 in SCC12 cells. These results revealed that the upregulation of NNMT induced cellular invasion via EMT?related gene expression in SCC cells.

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L1CAM Expression is Related to Non-Endometrioid Histology, and Prognostic for Poor Outcome in Endometrioid Endometrial Carcinoma.

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