title: Hypomethylation of long interspersed nuclear element-1 (LINE-1) is associated with poor prognosis via activation of c-MET in hepatocellular carcinoma.
abstract: BACKGROUND
  Long interspersed nuclear element-1 (LINE-1) methylation status, representing global DNA methylation levels, is associated with patient prognosis in several types of cancer. This study was designed to examine the prognostic significance of LINE-1 methylation in patients with hepatocellular carcinoma (HCC) and the possible mechanisms related to oncogene activation.
  
  
  METHODS
  Seventy-five HCC patients who underwent hepatectomy between 2006 and 2012 were enrolled in this study. Quantitative pyrosequencing was performed to quantify the methylation level of three CpG sites in the LINE-1 promoter. Clinicopathological variables and prognosis were compared between LINE-1 hypo- and hypermethylation groups. LINE-1-inserted c-MET (L1-MET) gene expression and its correlation with LINE-1 methylation levels also were analyzed.
  
  
  RESULTS
  LINE-1 was significantly hypomethylated in tumor tissues compared with nontumor tissues (48.3 ± 12.2 % vs. 68.2 ± 2.0 %, respectively, p < 0.0001). LINE-1 hypomethylation was not associated with any clinicopathological factors in HCC patients, except sex (p < 0.05). However, patients with LINE-1 hypomethylation exhibited significantly poorer outcome, and multivariate analysis revealed that LINE-1 hypomethylation was an independent risk factor for overall survival (hazard ratio (HR) = 6.1, p = 0.031) and disease-free survival (HR = 2.34, p = 0.045). L1-MET expression was significantly higher in tumor tissues (p < 0.01). L1-MET expression levels were inversely correlated with LINE-1 methylation levels, and positively correlated with c-MET expression (p < 0.05). Furthermore, higher c-MET protein expression was observed in the LINE-1 hypomethylated tumor tissues compared with hypermethylated tumor tissues (p = 0.032).
  
  
  CONCLUSIONS
  LINE-1 hypomethylation is significantly associated with poor prognosis in patients with HCC, possibly due to activation of c-MET expression.
authors.affiliation: Department of Surgery, The University of Tokushima, Tokushima, Japan.
authors.forename: Chengzhan
authors.initials: C
authors.lastname: Zhu
authors.forename: Tohru
authors.initials: T
authors.lastname: Utsunomiya
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ikemoto
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yamada
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morine
authors.forename: Satoru
authors.initials: S
authors.lastname: Imura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Arakawa
authors.forename: Chie
authors.initials: C
authors.lastname: Takasu
authors.forename: Daichi
authors.initials: D
authors.lastname: Ishikawa
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Shimada
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000235:genetics* / Q000601:surgery; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000601:surgery; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000235:genetics*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D019859:Proto-Oncogene Proteins c-met