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

Ji Xian Xiong, Yan Song Wang, Jingyi Sheng, Di Xiang, Tu Xiong Huang, Bin Bin Tan, Cui Mian Zeng, Hua Hui Li, Jiao Yang, Stephen J. Meltzer, Yuriko Mori, Yan Ru Qin, Xin Yuan Guan, Li Fu

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1658-1668
Number of pages11
JournalInternational Journal of Biological Sciences
Volume14
Issue number12
DOIs
StatePublished - Sep 9 2018

Keywords

  • Antioxidant gene
  • DNA methylation
  • Familial ESCC
  • Oxidative DNA damage
  • SLC22A3

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Xiong, J. X., Wang, Y. S., Sheng, J., Xiang, D., Huang, T. X., Tan, B. B., Zeng, C. M., Li, H. H., Yang, J., Meltzer, S. J., Mori, Y., Qin, Y. R., Guan, X. Y., & Fu, L. (2018). Epigenetic alterations of a novel antioxidant gene SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer. International Journal of Biological Sciences, 14(12), 1658-1668. https://doi.org/10.7150/ijbs.28482