PAX6 suppresses growth of human glioblastoma cells

Abstract

Purpose: Glioblastomas (GBMs) are the most common primary malignant brain tumors. Majority of GBMs has loss of heterozygosity of chromosome 10. The PAX6 encodes a transcription factor that involves in development of the brain, where its expression persists. We have reported that the expression of PAX6 was significantly reduced in GBMs and that a low level of PAX6 expression is a harbinger of an unfavorable prognosis for patients with malignant astrocytic glioma. Interestingly, PAX6 expression was increased in suppressed somatic cell hybrids derived from introducing a normal human chromosome 10 into U251 GBM cells. Thus it is interesting to determine if repression of PAX6 expression is involved in anti-tumor suppression function in GBM.

Experimental design: We overexpressed PAX6 in a GBM cell line U251HF via either stable transfection or infection with recombinant adenovirus, and examined cell growth in vitro and in vivo.

Result: Although we did not observe changes in the cell doubling time for PAX6-stable transfectants, significantly fewer numbers of PAX6-positive colonies grew in soft agar. Transient overexpression of PAX6 via adenovirus, however, suppressed cell growth by increasing the number of cells in G1 and by decreasing the number of cells in S-phase, and later on caused a dramatic level of cell death. Repeated subcutaneous and intracranial implantation experiments in nude mice using PAX6-stable transfectants provided solid evidence that PAX6 suppressed tumor growth in vivo and significantly extended mouse survival.

Conclusion: Our data demonstrate that PAX6exerts a tumor suppressor function that limits the growth of GBM cells.