Zhou Yi-Hong, Wu Xiaosong, Tan Fang, Shi Yue-Xi, Glass Tricia, Liu T J, Wathen Kyle, Hess Kenneth R, Gumin Joy, Lang Frederick, Yung W K Alfred
Department of Neurobiology and Developmental Sciences, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 753, Little Rock, AR 72205, USA.
J Neurooncol. 2005 Feb;71(3):223-9. doi: 10.1007/s11060-004-1720-4.
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.
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.
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.
Our data demonstrate that PAX6exerts a tumor suppressor function that limits the growth of GBM cells.
胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤。大多数GBM存在10号染色体杂合性缺失。PAX6编码一种参与脑发育的转录因子，其表达持续存在。我们曾报道，GBM中PAX6的表达显著降低，且低水平的PAX6表达是恶性星形细胞瘤患者预后不良的先兆。有趣的是，将正常人10号染色体导入U251 GBM细胞所获得的抑制性体细胞杂种中，PAX6表达增加。因此，确定PAX6表达的抑制是否参与GBM的抗肿瘤抑制功能很有意思。
我们通过稳定转染或重组腺病毒感染，在GBM细胞系U251HF中过表达PAX6，并检测其体外和体内的细胞生长情况。
虽然我们未观察到PAX6稳定转染细胞的细胞倍增时间有变化，但在软琼脂中生长的PAX6阳性集落数量显著减少。然而，通过腺病毒短暂过表达PAX6可通过增加G1期细胞数量和减少S期细胞数量来抑制细胞生长，随后导致显著水平的细胞死亡。使用PAX6稳定转染细胞在裸鼠中进行的重复皮下和颅内植入实验提供了确凿证据，表明PAX6在体内抑制肿瘤生长并显著延长小鼠生存期。
我们的数据表明，PAX6发挥肿瘤抑制功能，限制GBM细胞的生长。
