An integrated analysis of SOCS1 down-regulation in HBV infection-related hepatocellular carcinoma.
Persistent inflammation together with genetic/epigenetic aberrations is strongly associated with chronic Hepatitis B virus (HBV) infection-related hepatocarcinogenesis. Here, we investigated the alterations of the suppressor of cytokine signalling (SOCS) family genes in HBV-related hepatocellular carcinoma (HCC). A total of 116 patients with HCC were enrolled in this study. The methylation statuses of SOCS1-7 and CISH genes were quantitatively measured and clinicopathological significance of SOCS1 methylation was statistically analysed. The gene copy number variation was assayed by aCGH. Luciferase reporter assay and Western blot were used to detect the involvement of SOCS1 in p53 signalling. We found high frequencies of SOCS1 gene hypermethylation in both tumour (56.03%) and adjacent nontumour tissues (54.31%), but tumour tissues exhibited increased methylation intensity (24.01% vs 13.11%, P < 0.0001), particularly in patients with larger tumour size or cirrhosis background (P < 0.0001). In addition, the frequency and intensity of SOCS1 hypermethylation in tumour tissues were both significantly higher than those in nontumour tissues in male gender patients and in patients ≥45 years old (P = 0.0214 and P < 0.0001, P = 0.0232 and P < 0.0001, respectively). SOCS1 gene deletion was found in 8 of 25 aCGH assayed tumour specimens, which was associated with lower SOCS1 mRNA expression (P = 0.0448). Furthermore, ectopic SOCS1 overexpression could activate the p53 signalling pathway in HCC cell lines. Hypermethylation of SOCS2-7 and CISH genes was seldom found in HCC. Our results suggested that the gene loss and epigenetic silencing of SOCS1 were strongly associated with HBV-related HCC.
Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
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X
Zhang
J
J
Wang
J
J
Cheng
S
S
Ding
M
M
Li
S
S
Sun
L
L
Zhang
S
S
Liu
X
X
Chen
H
H
Zhuang
F
F
Lu
D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D018628:Gene Dosage; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D019694:Hepatitis B, Chronic / Q000150:complications*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis* / Q000235:genetics
D008156:Luciferases; D009687:Nuclear Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C108944:SOCS1 protein, human; C108775:SOCS7 protein, human
hepatitis B virus; hepatocellular carcinoma; methylation; p53; suppressor of cytokine signalling 1