Biological significance of CDKN2A-ARF inactivation of glioma and meningioma progression.

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It was shown that the p14 (alternating reading frame : ARF) gene was frequently deleted in the majority of p53 wild-type (WT) glioblastomas, suggesting that p14 (ARF) inactivation contributes to p53-WT glioma progression. p14 (ARF) protein binds to MDM2 and inhibits MDM2-mediated degradation of p53. To assess the biological significance of p14 (ARF) inactivation in glioma, we introduced an in vivo Doxycycline (DOX)-regulated inducible p14 (ARF) expression system to p14 (ARF)-negative cells. Human glioblastoma cell lines, U87MG (p14-deleted, p53-WT), U251MG (p14-deleted, p53-mutated) were used in this study. We established U87MG- or U251MG-derived clones with in vivo inducible p14 expression and injected subcutaneously into the bilateral flanks of nude mice in the presence of DOX. When the tumor volume reached to 60 mm^3, we divided mice into two groups; one is maintained with DOX (p14 expression -), and the other without DOX (p14 expression +). The size of tumors were examined and scored. Induction of p14 expression significantly suppressed the in vivo growth of U87MG cells. U251MG cells, however, grew regardless of p14 expression. These findings strongly indicated that exogenous p14 expression inhibits the proliferation of p53-WT glioma cells. Inactivation of p14 would play an important role in the enhancement of unregulated glioma growth in vivo.We found loss of p14 (ARF) expression in majority of anaplastic or atypical meningiomas. Meningiomas with the absence of p14 (ARF) expression exclusively showed homozygous deletion of not only the p14 (ARF) gene but also the CDKN2A gene. Both genes are located on chromosome 9p21. These results suggested that loss of p14 (ARF) - CDKN2A loci was associated with ARF/p53 and CDKN2A/RB pathway, leading to malignant transformation of meningioma cells.