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01-12-2014 | Translational Research and Biomarkers

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

Authors: Chengzhan Zhu, MD, Tohru Utsunomiya, MD, PhD, Tetsuya Ikemoto, MD, PhD, Shinichiro Yamada, MD, Yuji Morine, MD, PhD, Satoru Imura, MD, PhD, Yusuke Arakawa, MD, PhD, Chie Takasu, MD, PhD, Daichi Ishikawa, MD, Issei Imoto, MD, PhD, Mitsuo Shimada, MD, PhD

Published in: Annals of Surgical Oncology | Special Issue 4/2014

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.

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Title: Hypomethylation of Long Interspersed Nuclear Element-1 (LINE-1) is Associated with Poor Prognosis via Activation of c-MET in Hepatocellular Carcinoma
Authors: Chengzhan Zhu, MD
Tohru Utsunomiya, MD, PhD
Tetsuya Ikemoto, MD, PhD
Shinichiro Yamada, MD
Yuji Morine, MD, PhD
Satoru Imura, MD, PhD
Yusuke Arakawa, MD, PhD
Chie Takasu, MD, PhD
Daichi Ishikawa, MD
Issei Imoto, MD, PhD
Mitsuo Shimada, MD, PhD
Publication date: 01-12-2014
Publisher: Springer US
Published in: Annals of Surgical Oncology / Issue Special Issue 4/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-014-3874-4

At a glance: The STEP trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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