The levels of
insulin-like growth factor-binding protein 2 (IGFBP2) are elevated during progression of many human
cancers. By using a glial-specific transgenic mouse system (RCAS/Ntv-a), we reported previously that IGFBP2 is an oncogenic factor for
glioma progression in combination with
platelet-derived growth factor-beta (
PDGFB). Because the INK4a-ARF locus is often deleted in high-grade
gliomas (
anaplastic oligodendroglioma and
glioblastoma), we investigated the effect of the Ink4a-Arf-null background on IGFBP2-mediated progression of
PDGFB-initiated
oligodendroglioma. We demonstrate here that homozygous deletion of Ink4a-Arf bypasses the requirement of exogenously introduced IGFBP2 for
glioma progression. Instead, absence of Ink4a-Arf resulted in elevated endogenous
tumor cell IGFBP2. An inverse relationship between
p16(INK4a) and IGFBP2 expression was also observed in human
glioma tissue samples and in 90 different
cancer cell lines by using Western blotting and reverse-phase
protein lysate arrays. When endogenous IGFBP2 expression was attenuated by an RCAS vector expressing antisense IGFBP2 in our mouse model, a decreased incidence of
anaplastic oligodendroglioma as well as prolonged survival was observed. Thus,
p16(INK4a) is a negative regulator of the IGFBP2 oncogene. Loss of Ink4a-Arf results in increased IGFBP2, which contributes to
glioma progression, thereby implicating IGFBP2 as a marker and potential therapeutic target for Ink4a-Arf-deleted
gliomas.