2. Academic Validation
  3. DKK1 is epigenetically downregulated by promoter methylation and inhibits bile acid-induced gastric intestinal metaplasia

DKK1 is epigenetically downregulated by promoter methylation and inhibits bile acid-induced gastric intestinal metaplasia

  • Biochem Biophys Res Commun. 2020 Mar 12;523(3):780-786. doi: 10.1016/j.bbrc.2019.12.109.
Wenquan Lu 1,  Zhen Ni 2,  Mingfu Tong 3,  Shuqin Jiang 4,  Jian Zhang 5,  Chenchen Feng 6,  Chuan Han 7,  Ting Yuan 8,  Na Wang 9,  Jing Zhao 10,  Nina Sun 11,  Caifang Liu 12,  Qiaoyu Jia 13,  Qiong Wu 14,  Hanbing Ning 15,  Yongquan Shi 16
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China; State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: 1053045324@qq.com.
  • 2 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China; Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, China. Electronic address: hnjzj@126.com.
  • 3 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China. Electronic address: tongmingfu1983@163.com.
  • 4 Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. Electronic address: 1050185942@qq.com.
  • 5 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: 453544759@qq.com.
  • 6 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China; Xi'an Medical University, Xi'an, Shaanxi, 710021, China. Electronic address: 451620705@qq.com.
  • 7 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China; Department of Gastroenterology, Rocket Army Emei Sanatorium, Emei, Sichuan, 614200, China. Electronic address: hanchuan3012005173@126.com.
  • 8 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China; Department of Gastroenterology, The 150 Hospital of the People's Liberation Amy, Luoyang, Henan, 471000, China. Electronic address: 275887627@qq.com.
  • 9 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: 13201840712@163.com.
  • 10 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China; Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China. Electronic address: 2264480294@qq.com.
  • 11 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China; Xi'an Medical University, Xi'an, Shaanxi, 710021, China. Electronic address: snn42409909@163.com.
  • 12 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China; Xi'an Medical University, Xi'an, Shaanxi, 710021, China. Electronic address: liucaifang0515@163.com.
  • 13 Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China. Electronic address: jqy881314@sina.com.
  • 14 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: fengling00909@163.com.
  • 15 Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China. Electronic address: nhbing419@qq.com.
  • 16 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: shiyquan@fmmu.edu.cn.
PMID: 31952791 DOI: 10.1016/j.bbrc.2019.12.109
Abstract

Dickkopf-related protein 1 (DKK1) is essential to gastric Cancer as an inhibitor of Wnt signaling. Gastric intestinal metaplasia (GIM) is an important precancerous lesion of gastric Cancer that can be activated by bile acid reflux and chronic inflammation. However, the exact mechanism of DKK1 in bile acid-induced GIM has not been completely elucidated. We aimed to explore the epigenetic alterations and biological functions of DKK1 in the development of GIM. In the present study, bile acid was found to induce the expression of intestinal markers in gastric epithelial cells, whereas DKK1 was downregulated in response to bile acid stimulation. The mRNA and protein expression levels of DKK1 were decreased in GIM tissues as evidenced by qRT-PCR and immunohistochemical staining. Surprisingly, the methylation of the DKK1 promoter increased in GIM tissues, and we discovered 28 differential methylation sites of the DKK1 promoter in GIM tissues. Bile acid was able to induce the partial methylation of the DKK1 promoter, while 5-aza could increase DKK1 expression as well as decrease intestinal markers expression in gastric epithelial cells. In conclusion, the promoter methylation and downregulation of DKK1 might play important roles in the development of GIM, especially bile acid-induced GIM.

Keywords

Bile acid; CDX2; Dickkopf-related protein 1(DKK1); Gastric cancer; Gastric intestinal metaplasia; Methylation.

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