DOI QR코드

DOI QR Code

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induces Retinoic Acid Receptor β Hypermethylation through DNA Methyltransferase 1 Accumulation in Esophageal Squamous Epithelial Cells

  • Wang, Jing (Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University) ;
  • Zhao, Shu-Lei (Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University) ;
  • Li, Yan (Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University) ;
  • Meng, Mei (Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University) ;
  • Qin, Cheng-Yong (Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University)
  • 발행 : 2012.05.30

초록

Overexpression of DNA methyltransferase 1 (DNMT1) has been detected in many cancers. Tobacco exposure is known to induce genetic and epigenetic changes in the pathogenesis of malignancy. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is an important carcinogen present in tobacco smoke; however the detailed molecular mechanism of how NNK induces esophageal carcinogenesis is still unclear. We found that DNMT1 was overexpressed in ESCC tissues compared with paired non-cancerous tissues, the overexpression being correlated with smoking status and low expression of $RAR{\beta}$. The latter could be upregulated by NNK treatment in Het-1A cells, and the increased DNMT1 expression level reflected promoter hypermethylation and downregulation of retinoic acid receptor ${\beta}$($RAR{\beta}$). RNA interference mediated knockdown of DNMT1 resulted in promoter demethylation and upregulation of $RAR{\beta}$ in KYSE30 and TE-1 cells. 3-(4,5-Dimethyl-thiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometric analysis demonstrated that NNK treatment in Het-1A cells could enhance cell proliferation and inhibit cell apoptosis in a dose-dependent manner. In conclusion, DNMT1 overexpression is correlated with smoking status and low expression of $RAR{\beta}$ in esophageal SCC patients. NNK could induce $RAR{\beta}$ promoter hypermethylation through upregulation of DNMT1 in esophageal squamous epithelial cells, finally leading to enhancement of cell proliferation and inhibition of apoptosis.

키워드

참고문헌

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피인용 문헌

  1. 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone Promotes Esophageal Squamous Cell Carcinoma Growth via Beta-Adrenoceptors In Vitro and In Vivo vol.10, pp.3, 2015, https://doi.org/10.1371/journal.pone.0118845
  2. Association of Methylation of the RAR-β Gene with Cigarette Smoking in Non-Small Cell Lung Cancer with Southern-central Chinese Population vol.15, pp.24, 2015, https://doi.org/10.7314/APJCP.2014.15.24.10937
  3. Tobacco carcinogen NNK-induced lung cancer animal models and associated carcinogenic mechanisms vol.47, pp.7, 2015, https://doi.org/10.1093/abbs/gmv041
  4. Molecular landscape of esophageal cancer: implications for early detection and personalized therapy pp.00778923, 2018, https://doi.org/10.1111/nyas.13876