Abstract
BackgroundWnt inhibitory factor-1(WIF-1) acts as a Wnt-antagonists and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression activate Wnt signaling aberrantly and induce the development of various human tumors. With this work we intended to investigate the expression and promoter methylation status of WIF-1 gene in human astrocytomas.MethodsThe tissue samples consisted of 53 astrocytomas and 6 normal brain tissues. The expression levels of WIF-1 were determined by immunohistochemistry and semiquantitative RT-PCR. The results were analyzed in correlation with clinicopathological data. Methylation status of WIF-1 gene promoter was investigated using methylation specific PCR. The relationship between methylation and expression of the genes was analyzed.ResultsThe average expression levels of WIF-1 protein and mRNA in astrocytomas were decreased significantly compared with normal control tissues. The protein and mRNA expression of WIF-1 gene in astrocytomas was decreased with the increase of pathological grade. Furthermore, WIF-1 promoter methylation was observed by MS-PCR in astrocytomas which showed significant reduction of WIF-1 expression. The WIF-1 promoter hypermethylation was associated with reduced expression of WIF-1 expression.ConclusionOur results demonstrate that the WIF-1 gene is frequently down-regulated or silenced in astrocytomas by aberrant promoter methylation. This may be an important mechanism in astrocytoma carcinogenesis.
Highlights
Wnt inhibitory factor-1(WIF-1) acts as a Wnt-antagonists and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression activate Wnt signaling aberrantly and induce the development of various human tumors
We describe for the first time that the expression of WIF-1 was frequently downregulated by its promoter hypermethylation in astrocytomas compared with normal tissue samples, which might contribute to the upregulation of Wnt/bcatenin signaling in astrocytoma carcinogenesis
Expression of WIF-1 protein To detect the expression level of WIF-1, immunohistochemistry was performed in 6 normal brain tissues and in 53 astrocytoma tissues (Tab. 1 and Fig. 1)
Summary
Wnt inhibitory factor-1(WIF-1) acts as a Wnt-antagonists and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression activate Wnt signaling aberrantly and induce the development of various human tumors. With this work we intended to investigate the expression and promoter methylation status of WIF-1 gene in human astrocytomas. Despite recent advances in diagnosis and therapies such as surgery, radiation, and chemotherapy, the prognosis and survival times of highgrade astrocytomas(WHO grade III, IV)remains poor. The median survival is only 12 to 15 months for patients with glioblastoma(WHO grade IV)and 2 to 5 years for patients with anaplastic astrocytoma(WHO grade III)[1]. There are several reports which evident the involvement of Wnt/b-catenin signaling in astrocytomas [2,3,4,5]. Wnt inhibitory factor-1 (WIF-1) is identified as one of the secreted antagonists that can
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