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.
Yang
Zhuanyi
Z
Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, China.
Wang
Ying
Y
Fang
Jiasheng
J
Chen
Fenghua
F
Liu
Jingfang
J
Wu
Jun
J
Wang
Yanjin
Y
Song
Tao
T
Zeng
Feiyue
F
Rao
Yihua
Y
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