Circulating Methylated XAF1 DNA Indicates Poor Prognosis for Gastric Cancer
Ling Z.-Q. Lv P. Lu X.-X. Yu J.-L. Han J. Ying L.-S. Zhu X. Zhu W.-Y. Fang X.-H. Wang S.
Ling Z.-Q.
Lv P.
Lu X.-X.
Yu J.-L.
Han J.
Ying L.-S.
Zhu X.
Zhu W.-Y.
Fang X.-H.
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Abstract
Background:Methylated DNA in fluids may be a suitable biomarker for cancer patients. XAF1 has been shown to be frequently down-regulated in human gastric cancer (GC). Here, we investigated if XAF1 methylation in GC could be a useful biomarker.Methods:Real-time RT-PCR was used to detect XAF1 mRNA expression; immunohistochemistry and western blot were used to examine XAF1 protein expression in GC tissues (n = 202) and their corresponding para-cancerous histological normal tissues (PCHNTs). Real-time methylation specific-PCR was used to investigate XAF1 promoter methylation in the same panel of GC tissues, their PCHNTs and sera.Results:We confirmed frequent XAF1 down-regulation in both mRNA and protein levels in GC tissues as compared to normal controls and PCHNTs. XAF1 hypermethylation was evidenced in 83.2% (168/202) of GC tissues and 27.2% (55/202) of PCHNTs, while no methylation was detected in the 88 normal controls. The methylation level in GC tissues was significantly higher than that in PCHNTs (p<0.05). The hypermethylation of XAF1 significantly correlated with the down-regulation of XAF1 in GC tissues in both mRNA and protein levels (p<0.001 each). Moreover, we detected high frequency of XAF1 methylation (69.8%, 141 out of 202) in the sera DNAs from the same patients, while the sera DNAs from 88 non-tumor controls were negative for XAF1 methylation. The XAF1 methylation in both GC tissues and in the sera could be a good biomarker for diagnosis of GC (AUC = 0.85 for tissue and AUC = 0.91 for sera) and significantly correlated with poorer prognosis (p<0.001). In addition, after-surgery negative-to-positive transition of XAF1 methylation in sera strongly associated with tumor recurrence.Conclusions:1) Dysfunction of XAF1 is frequent and is regulated through XAF1 promoter hypermethylation; 2) Detection of circulating methylated XAF1 DNAs in the serum may be a useful biomarker in diagnosis, evaluating patient's outcome (prognosis and recurrence) for GC patients. © 2013 Ling et al.
Keywords
DNA, messenger RNA, protein XAF1, tumor marker, unclassified drug, messenger RNA, signal peptide, tumor marker, tumor protein, XAF1 protein, human, adult, article, cancer patient, cancer prognosis, DNA methylation, down regulation, female, human, human cell, human tissue, immunohistochemistry, major clinical study, male, protein expression, reverse transcription polymerase chain reaction, stomach cancer, tumor recurrence, Western blotting, blood, gene expression regulation, genetics, metabolism, middle aged, pathology, physiology, prognosis, promoter region, Stomach Neoplasms, tumor cell line, tumor volume, Biomarkers, Tumor, Cell Line, Tumor, DNA Methylation, Down-Regulation, Female, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, Neoplasm Proteins, Neoplasm Recurrence, Local, Prognosis, Promoter Regions, Genetic, RNA, Messenger, Stomach Neoplasms, Tumor Burden
Source Title
PLoS ONE
Publisher
Series/Report No.
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Rights
Attribution 4.0 International
Date
2013
DOI
10.1371/journal.pone.0067195
Type
Article