Downregulation of WIF-1 by hypermethylation in astrocytomas.
Wnt inhibitory factor-1 (WIF-1) acts as a Wnt antagonist and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression of WIF-1 activate Wnt signaling aberrantly and induce the development of several human tumors. By using RT-PCR, immunohistochemistry and methylation-specific PCR, we analyzed the expression and methylation of WIF-1 in 4 normal brain tissues, 35 freshly resected astrocytoma tissues and 4 glioblastoma-derived cell lines. Significant downregulation of WIF-1 mRNA and protein expression levels was observed in astrocytoma tissues compared with normal brain tissues. Significant association between WIF-1 downregulation and pathological grade of astrocytomas was found. WIF-1 gene aberrant methylation was observed in 19 of 35 (54.29%) tumor samples. The promoter methylation tumors showed low WIF-1 protein and mRNA expression, whereas the promoter unmethylation tumors displayed high protein and mRNA expression levels. Moreover, complete absence of WIF-1 mRNA expression was observed in four cell lines, whereas treatment with demethylating agent, 5-aza-2'-deoxycytidine, restored WIF-1 expression. Our results suggested that the WIF-1 gene is frequently silenced in astrocytoma by aberrant promoter methylation. This may be an important mechanism in astrocytoma carcinogenesis.
Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, China.
Zhuanyi
Z
Yang
Ying
Y
Wang
Jiasheng
J
Fang
Fenghua
F
Chen
Jingfang
J
Liu
Jun
J
Wu
Yanjin
Y
Wang
Tao
T
Song
Feiyue
F
Zeng
Yihua
Y
Rao
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D001254:Astrocytoma / Q000235:genetics*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D012333:RNA, Messenger; D012097:Repressor Proteins; C485569:WIF1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D000077209:Decitabine; D001374:Azacitidine