Annals of Surgical Oncology

, Volume 21, Supplement 4, pp 729–735 | Cite as

Hypomethylation of Long Interspersed Nuclear Element-1 (LINE-1) is Associated with Poor Prognosis via Activation of c-MET in Hepatocellular Carcinoma

  • Chengzhan Zhu
  • Tohru Utsunomiya
  • Tetsuya Ikemoto
  • Shinichiro Yamada
  • Yuji Morine
  • Satoru Imura
  • Yusuke Arakawa
  • Chie Takasu
  • Daichi Ishikawa
  • Issei Imoto
  • Mitsuo ShimadaEmail author
Translational Research and Biomarkers



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.


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.


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).


LINE-1 hypomethylation is significantly associated with poor prognosis in patients with HCC, possibly due to activation of c-MET expression.


Methylation Level Nontumor Tissue Adjacent Nontumor Liver Tissue Biotinylated Polymerase Chain Reaction Product 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We declare that no conflict of interest exist.

Supplementary material

10434_2014_3874_MOESM1_ESM.tif (2.6 mb)
Supplementary Fig. 1 Representative LINE-1 hypermethylated nontumors (methylation level, 30.7 %) and hypomethylated tumors (methylation level, 68.3 %). The arrows indicate no residual C at the non-CpG site, ensuring complete bisulfite conversion
10434_2014_3874_MOESM2_ESM.tif (16.1 mb)
Supplementary Fig. 2a Correlation of L1-MET expression and LINE-1 methylation levels in tumors (n = 53, R = −0.34, p = 0.01). b Correlation of L1-MET expression with c-MET expression in tumor tissue (R = 0.58, p < 0.05). c Representative immunohistochemical staining for c-MET expression. Left indicates high and right indicates low c-MET expression


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Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Chengzhan Zhu
    • 1
  • Tohru Utsunomiya
    • 1
  • Tetsuya Ikemoto
    • 1
  • Shinichiro Yamada
    • 1
  • Yuji Morine
    • 1
  • Satoru Imura
    • 1
  • Yusuke Arakawa
    • 1
  • Chie Takasu
    • 1
  • Daichi Ishikawa
    • 1
  • Issei Imoto
    • 2
  • Mitsuo Shimada
    • 1
    Email author
  1. 1.Department of SurgeryThe University of TokushimaTokushimaJapan
  2. 2.Department of Human GeneticsThe University of TokushimaTokushimaJapan

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