Epigenetic alterations of a novel antioxidant gene SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer

Int J Biol Sci. 2018 Sep 7;14(12):1658-1668. doi: 10.7150/ijbs.28482. eCollection 2018.


Esophageal squamous cell carcinoma (ESCC) occurs with the highest frequency in China, especially in the high-risk Northern Chinese. Recent studies have reported that SLC22A3 is significantly downregulated in non-tumor (NT) esophageal tissues from familial ESCC patients compared with those from sporadic ESCC. However, the mechanism of how SLC22A3 regulates familial ESCC remains unknown. In this study, post hoc genome-wide association studies (GWAS) in 496 cases with a family history of upper gastrointestinal tract cancers and 1056 controls were performed and the results revealed that SLC22A3 is a novel susceptibility gene for familial ESCC. Reduced expression of SLC22A3 in NT esophageal tissues from familial ESCC patients significantly correlates with its promoter hypermethylation. Moreover, case-control study of Chinese descendants from different risk areas of China revealed that the methylation of the SLC22A3 gene in peripheral blood leukocyte (PBL) DNA samples could be a risk factor for developing ESCC in this high-risk population. Functional studies showed that SLC22A3 is a novel antioxidant gene, and deregulation of SLC22A3 facilitates heat stress-induced oxidative DNA damage and formation of γ-H2AX foci in normal esophageal epithelial cells. Collectively, we show that epigenetic alterations of SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer.

Keywords: Familial ESCC - SLC22A3 - DNA methylation - antioxidant gene -oxidative DNA damage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Blotting, Western
  • Case-Control Studies
  • DNA Damage / genetics
  • DNA Methylation / genetics
  • Epigenesis, Genetic / genetics*
  • Esophageal Neoplasms / genetics*
  • Female
  • Fluorescent Antibody Technique
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods*
  • Heat-Shock Response
  • Humans
  • Lentivirus / genetics
  • Male
  • Middle Aged
  • Models, Biological
  • Organic Cation Transport Proteins / genetics*
  • Promoter Regions, Genetic / genetics
  • Reactive Oxygen Species / metabolism


  • Organic Cation Transport Proteins
  • Reactive Oxygen Species
  • solute carrier family 22 (organic cation transporter), member 3