title: XRCC1 downregulated through promoter hypermethylation is involved in human gastric carcinogenesis.
abstract: OBJECTIVE
  To analyze the expression and aberrant methylation of X-ray repair cross-complementing gene 1 (XRCC1) in gastric carcinogenesis, and identify the molecular mechanism of gastric carcinogenesis.
  
  
  METHODS
  The method based on methyl binding domain protein (MBD) immuno-precipitation and promoter microarray was employed to screen the gastric cancer-related methylation-sensitive gene. An immunohistochemistry assay was applied to detect the protein expression of XRCC1 in the multistep progression of gastric carcinogenesis. The mRNA expression of XRCC1 was determined by real-time PCR in tumor tissues and their corresponding non-tumorous tissues. The methylation status and Arg194Trp and Arg399Gln polymorphisms of XRCC1 in gastric cancer and gastritis tissues were analyzed by methylation-specific PCR, bisulfite genomic sequencing and direct DNA sequencing, respectively.
  
  
  RESULTS
  Promoter microarray screening and identification suggested that XRCC1 was a methylation-sensitive gene. Immunochemistry results showed that XRCC1 protein expression gradually decreased with progression of gastric mucosal lesions (P < 0.05). The positive rate of XRCC1 in patients with well/moderately differentiated gastric cancer was significantly higher than patients with poorly differentiated gastric cancer (P < 0.05). The mRNA expression of XRCC1 in gastric cancer tissues was significantly lower than that in the non-tumorous tissues (P < 0.05). Meanwhile, XRCC1 methylation in gastric cancer tissues was more frequent than that in the gastritis tissues (P < 0.05), and the downregulation of XRCC1 expression was relevant to methylation (P < 0.05).
  
  
  CONCLUSIONS
  The expression of XRCC1 is downregulated in gastric carcinogenesis, and promoter hypermethylation may be one of the mechanisms contributing to its downregulation.
authors.affiliation: Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Jie Ting
authors.initials: JT
authors.lastname: Tang
authors.forename: Yan Shen
authors.initials: YS
authors.lastname: Peng
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Chen
authors.forename: Yan Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Jing Yuan
authors.initials: JY
authors.lastname: Fang
mesh_terms: D001706:Biopsy; D019175:DNA Methylation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000502:physiology; D005756:Gastritis / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human