Abstract
Nicotinamide N-methyltransferase (NNMT) is an important methyltransferase involved in the biotransformation of many drugs and exogenous compounds. Abnormal expression of NNMT protein is closely associated with the onset and progression of many malignancies, but little is known about its role in esophageal squamous cell carcinoma (ESCC). Therefore, we aimed to explore whether NNMT plays any roles in carcinogenesis and metastasis in ESCC. NNMT expression was determined by immunohistochemistry in ESCC and corresponding adjacent normal tissues. Functional experiments were performed to elucidate the effects of NNMT knockdown on the proliferation, apoptosis, cell cycle, migration, and epithelial-mesenchymal transition (EMT) in EC9706 and TE1 cells. NNMT expression was significantly elevated in ESCC tissues compared with corresponding adjacent normal tissues. Moreover, a significant association emerged between NNMT expression and lymph node metastasis. SiRNA-mediated knockdown of NNMT in ESCC cells can significantly suppress cell viability and migration, induce cell cycle arrest, and promote cell apoptosis. In addition, NNMT downregulation led to the reversal of EMT, as reflected by upregulation of the intercellular adhesion molecule E-cadherin and downregulation of the mesenchymal markers N-cadherin and Vimentin. Further study found that NNMT knockdown suppressed the Wnt/β-catenin signaling pathway. Taken together, these findings indicate that NNMT is a critical regulator of EMT in ESCC and may be a potential therapeutic target for ESCC metastasis.
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18 July 2020
A Correction to this paper has been published: https://doi.org/10.1007/s11010-020-03829-0
08 February 2024
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s11010-024-04959-5
References
Chen W, Zheng R, Zuo T et al (2012) National cancer incidence and mortality in China. Chin J Cancer Res 28(1):1–11
Pennathur A, Gibson MK, Jobe BA et al (2013) Oesophageal carcinoma. LANCET 381(9864):400–412
Zeng H, Zheng R, Zhang S et al (2016) Esophageal cancer statistics in China, 2011: estimates based on 177 cancer registries. Thorac Cancer 7(2):232–237
Wang H, Deng F, Liu Q et al (2017) Prognostic significance of lymph node metastasis in esophageal squamous cell carcinoma. Pathol Res Pract 213(7):842–847
Haslehurst AM, Koti M, Dharsee M et al (2012) EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer 12:91
Feng H, Liu Q, Zhang N et al (2013) Leptin promotes metastasis by inducing an epithelial-mesenchymal transition in A549 lung cancer cells. Oncol Res 21(3):165–171
Chen C, Wang X, Huang X et al (2016) Nicotinamide N-methyltransferase: a potential biomarker for worse prognosis in gastric carcinoma. Am J Cancer Res 6(3):649–663
Aksoy S, Szumlanski CL, Weinshilboum RM (1994) Human liver nicotinamide N-methyltransferase. cDNA cloning, expression, and biochemical characterization. J Biol Chem 269(20):14835–14840
Xu JM, Moatamed F, Caldwell JS et al (2003) Enhanced expression of nicotinamide N-methyltransferase in human papillary thyroid carcinoma cells. J Clin Endocrinol Metab 88(10):4990–4996
Yao M, Tabuchi H, Nagashima Y et al (2005) Gene expression analysis of renal carcinoma: adipose differentiation-related protein as a potential diagnostic and prognostic biomarker for clear-cell renal carcinoma. J Pathol 205(3):377–387
Kim J, Hong SJ, Lim EK et al (2009) Expression of nicotinamide N-methyltransferase in hepatocellular carcinoma is associated with poor prognosis. J Exp Clin Cancer Res 28:20
Roessler M, Rollinger W, Palme S et al (2005) Identification of nicotinamide N-methyltransferase as a novel serum tumor marker for colorectal cancer. Clin Cancer Res 11(18):6550–6557
Emanuelli M, Santarelli A, Sartini D et al (2010) Nicotinamide N-methyltransferase upregulation correlates with tumour differentiation in oral squamous cell carcinoma. Histol Histopathol 25(1):15–20
Sartini D, Morganti S, Guidi E et al (2013) Nicotinamide N-methyltransferase in non-small cell lung cancer: promising results for targeted anti-cancer therapy. Cell Biochem Biophys 67(3):865–873
Loos M, Hedderich DM, Ottenhausen M et al (2009) Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer. BMC Cancer 9:463
Yu T, Wang Y-T, Chen P et al (2015) Effects of nicotinamide N-methyltransferase on PANC-1 cells proliferation, metastatic potential and survival under metabolic stress. Cell Physiol Biochem 35(2):710–721
Tang S-W, Yang T-C, Lin W-C et al (2011) Nicotinamide N-methyltransferase induces cellular invasion through activating matrix metalloproteinase-2 expression in clear cell renal cell carcinoma cells. Carcinogenesis 32(2):138–145
Wu Y, Siadaty MS, Berens ME et al (2008) Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration. Oncogene 27(52):6679–6689
Pozzi V, Mazzotta M, Lo Muzio L et al (2011) Inhibiting proliferation in KB cancer cells by RNA interference-mediated knockdown of nicotinamide N-methyltransferase expression. Int J Immunopathol Pharmacol 24(1):69–77
Zhang J, Wang Y, Li G et al (2014) Down-regulation of nicotinamide N-methyltransferase induces apoptosis in human breast cancer cells via the mitochondria-mediated pathway. PLoS ONE 9(2):e89202
Davis FM, Stewart TA, Thompson EW et al (2014) Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci 35(9):479–488
Liang L, Zeng M, Pan H et al (2018) Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-beta 1 expression. Oncol Lett 15(4):4592–4598
Douchi D, Ohtsuka H, Ariake K et al (2015) Silencing of LRRFIP1 reverses the epithelial-mesenchymal transition via inhibition of the Wnt/beta-catenin signaling pathway. Cancer Lett 365(1):132–140
Zhang J, Wen X, Ren X-Y et al (2016) YPEL3 suppresses epithelial-mesenchymal transition and metastasis of nasopharyngeal carcinoma cells through the Wnt/beta-catenin signaling pathway. J Exp Clin Cancer Res 35:109
Lu Y-J, Geng Z-J, Sun X-Y et al (2015) Isoprenaline induces epithelial-mesenchymal transition in gastric cancer cells. Mol Cell Biochem 408(1–2):1–13
Scaglia N, Igal RA (2008) Inhibition of Stearoyl-CoA Desaturase 1 expression in human lung adenocarcinoma cells impairs tumorigenesis. Int J Oncol 33(4):839–850
Acknowledgements
This study was supported by Henan Natural Science Foundation (Grant No. 182300410377), the Key Scientific Research Projects of Henan Higher Education institutions (Grant No. 17A180016), and the National Natural Science Foundation of China (Grant No. 81272691).
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Cui, Y., Zhang, L., Wang, W. et al. RETRACTED ARTICLE: Downregulation of nicotinamide N-methyltransferase inhibits migration and epithelial-mesenchymal transition of esophageal squamous cell carcinoma via Wnt/β-catenin pathway. Mol Cell Biochem 460, 93–103 (2019). https://doi.org/10.1007/s11010-019-03573-0
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DOI: https://doi.org/10.1007/s11010-019-03573-0