IGF-2 binding protein-3 (IGF2BP3) is a glioblastoma-specific marker which activates PI3-kinase/map-kinase pathways by modulating IGF-2

Abstract

Glioblastoma is the most common and malignant form of primary astrocytoma with a short median survival time despite advances in our understanding. Upon investigation of the IGF pathway, we found IGF2BP3/IMP3 transcript and protein to be up-regulated in GBMs but not in lower grade astrocytomas (p < 0.0001). IMP3 is a RNA binding protein known to bind to the 5-prime untranslated region of IGF-2 mRNA thereby activating its translation. Over-expression and knock-down based studies establish a role for IMP3 in promoting proliferation, anchorage-independent growth, invasion and chemoresistance. IMP3 over-expressing B16F10 cells also showed increased tumor growth, angiogenesis and metastasis resulting in poor survival in a mouse model. Additionally, the infiltrating front, perivascular and subpial regions in a majority of the GBMs stained positive for IMP3. A mouse model of glioma further substantiated these findings. IMP3-positive glioblastoma patients (n=83) in a prospectively studied cohort of patients showed poor survival upon univariate analysis (p=0.0441). In agreement with the translation activation functions of IMP3, we also found increased IGF-2 protein in GBMs without a corresponding increase in its transcript levels. Further, in vitro IMP3 knock-down, lowered the IGF-2 protein levels without altering its transcript levels. Concordantly, PI3-kinase and MAP-kinase, the downstream effectors of IGF-2, are activated by IMP3 and are found to be essential for IMP3-induced cell proliferation. Thus, we have identified IMP3 as a GBM-specific pro-proliferative and pro-invasive marker acting through the PI3-kinase and MAP-kinase pathways with a probable prognostic role in GBM patient survival.