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Frequent concomitant epigenetic silencing of SOX 1 and secreted frizzled‐related proteins ( SFRP s) in human hepatocellular carcinoma
Author(s) -
Shih YuLueng,
Hsieh ChungBao,
Yan MingDe,
Tsao ChunMing,
Hsieh TsaiYuan,
Liu ChangHsin,
Lin YaWen
Publication year - 2013
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.12078
Subject(s) - methylation , hepatocellular carcinoma , dna methylation , cancer research , epigenetics , microbiology and biotechnology , gene silencing , medicine , bisulfite sequencing , promoter , biology , gene expression , gene , genetics
Background and Aim Except for genetic mutations, epigenetic changes are also involved in the development of human cancers. Recently, we have identified SOX 1 , SRY (sex determining region Y )‐box 1, is hypermethylated in cervical cancer and ovarian cancer. Therefore, we investigated whether promoter hypermethylation of SOX 1 is common in hepatocellular carcinoma ( HCC ). Methods We used methylation‐specific polymerase chain reaction ( MS ‐ PCR ) and bisulfite sequencing to analyze the methyaltion level of the SOX 1 promoter in seven HCC cell lines, 54 clinical HCC s, 42 cirrhotic livers, 21 livers with chronic hepatitis, and 15 control livers. Then, we employed quantitative MS ‐ PCR ( QMSP ) to validate in an independent set of samples (60 paired HCC s and 30 control livers). Finally, we used luciferase reporter and colony formation assay to check the effect of SOX 1 in HCC . Results Promoter methylation of SOX 1 was significantly frequent in HCC cell lines and clinical HCC s, cirrhotic livers, but not in control livers ( P < 0.0001). There is a significant correlation between downregulation of SOX 1 expression and promoter methylation. QMSP results confirmed that promoter hypermethylation of SOX 1 is significantly more frequent in HCC s than control livers ( P < 0.0001). The frequency of SOX 1 methylation in patients with secreted frizzled‐related proteins ( SFRP s) methylation is significantly higher than in patients without SFRP s methylation ( P < 0.0001). Furthermore, ectopic expression of SOX 1 could suppress T ‐cell factor‐dependent transcriptional activity and colony formation number in HCC s. Conclusions Concomitant epigenetic silencing of SOX 1 and SFRP s through promoter hypermethylation is frequent in HCC s, and this might contribute to abnormal activation of canonical Wnt signal pathway.