Wip1 over-expression correlated with TP53/p14(ARF) pathway disruption in human astrocytomas.

PURPOSE: Wip1 over-expression inhibits p53 function and reduces selection for TP53 mutations during cancer progression. To clarify the correlation of Wip1 with TP53/p14(ARF) pathway disruption in astyrocytomas, the expression of Wip1 and TP53/p14(ARF) pathway alterations have been investigated.

METHODS: Tumor samples of 52 patients of astrocytomas were examined for TP53 mutations, p14(ARF) expression, and Wip1 expression. Direct sequencing of region from exons 5 to 8 of the TP53 gene was performed on the genomic DNA in each sample. The DNA methylation states of the CpG islands of the p14(ARF) gene were determined by MSP. The expression of Wip1 was analyzed by real-time quantitative PCR, Western blot, and immunohistochemical staining.

RESULTS: Disruption of the TP53/p14ARF pathway was detected in 57.7% of samples. Among 22 cases without TP53 and p14ARF alterations, 11 (50%) had Wip1 mRNA over-expression. In tumors with wild-type TP53 and p14ARF, Wip1 mRNA was over-expressed only 1 case out of 30 (3.3%). Higher levels of Wip1 were associated with TP53 mutations but not with lower levels of expression of p14(ARF) or aberrant promoter hypermethylation of the p14(ARF) gene.

CONCLUSION: Wip1 is selectively over-expressed in astyrocytomas without alterations in TP53 or p14(ARF). Wip1 may inhibit the TP53/p14(ARF) pathway.