J Cancer 2021; 12(20):6170-6181. doi:10.7150/jca.56419 This issue

Research Paper

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

Jun Yang1,2,3,4*, Qingchao Tong1,2*, Ying Zhang1,2, Shijin Yuan1,2, Yuzhen Gao1,2, Ke Deng5, Yanzhong Wang1,2, Jie Lu1,2, Xinyou Xie1,2, Zhe Zhang3✉, Jun Zhang1,2✉

1. Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou 310016, Zhejiang, People's Republic of China
2. Key Laboratory of Biotherapy of Zhejiang Province, 3 East Qingchun Road, Hangzhou 310016, Zhejiang, People's Republic of China
3. Ningbo Diagnostic Pathology Center, 685 North Huancheng Road, Ningbo 315010, Zhejiang, People's Republic of China
4. Department of Pathology, Ningbo Medical Center Lihuili Hospital, 57 Xingning Road, Ningbo 315040, Zhejiang, People's Republic of China
5. Department of colorectal surgery, Ningbo Medical Center Lihuili Hospital, 57 Xingning Road, Ningbo 315040, Zhejiang, People's Republic of China
*These authors contributed equally to this work

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Citation:
Yang J, Tong Q, Zhang Y, Yuan S, Gao Y, Deng K, Wang Y, Lu J, Xie X, Zhang Z, Zhang J. Overexpression of Nicotinamide N-methyltransferase mainly covers stroma of colorectal cancer and correlates with unfavorable survival by its product 1-MNA. J Cancer 2021; 12(20):6170-6181. doi:10.7150/jca.56419. Available from https://www.jcancer.org/v12p6170.htm

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Abstract

Graphic abstract

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.

Keywords: Nicotinamide N-methyltransferase, colorectal cancer, tumor stroma, survival, metastasis, 1-methyl-nicotinamide