Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Canada.
J Neuropathol Exp Neurol. 2011 Jun;70(6):430-7. doi: 10.1097/NEN.0b013e31821b94db.
To determine whether the zinc finger transcription factors GLI1 to GLI3 and suppressor of fused (SUFU) components of the Sonic hedgehog signaling pathway may be prognostic markers and potential therapeutic targets in pediatric medulloblastoma (MB), we investigated the relationship of the expression of these proteins to prognosis in the MB of 124 patients who had undergone surgery at the Hospital for Sick Children (Toronto, Ontario, Canada). The expressions of GLI1 (p = 0.011) and GLI2 (p = 0.003), but not of GLI3 (p = 0.774) or SUFU (p = 0.137), in the MB were associated with a worse overall survival by Kaplan-Meier analysis. Overall survival of patients positive for GLI1 and GLI2 was 6.01 ± 0.85 years and 5.27 ± 1.44 years, respectively, versus 10.11 ± 1.52 years and 10.18 ± 0.22 years for patients negative for GLI1 and GLI2, respectively. Knockdown of GLI2 in 3 MB cell lines resulted in decreased cell number and viability, as determined by the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay; knockdown of GLI1 had no effect. The decrease in cell number with GLI2 knockdown was caused by G0 cell cycle arrest; there was no induction of apoptosis. These results suggest that targeting the Sonic hedgehog pathway in positive patients may be a useful adjuvant therapeutic strategy for MB.
为了确定锌指转录因子 GLI1 到 GLI3 和 Sonic hedgehog 信号通路的抑制因子 SUFU 是否可能成为儿科髓母细胞瘤（MB）的预后标志物和潜在治疗靶点，我们研究了 124 名在加拿大安大略省多伦多 Sick Kids 医院接受手术的 MB 患者的这些蛋白的表达与预后的关系。通过 Kaplan-Meier 分析发现，MB 中 GLI1（p = 0.011）和 GLI2（p = 0.003）的表达与总生存率较差有关，但 GLI3（p = 0.774）或 SUFU（p = 0.137）的表达与总生存率无关。GLI1 和 GLI2 阳性患者的总生存率分别为 6.01 ± 0.85 年和 5.27 ± 1.44 年，而 GLI1 和 GLI2 阴性患者的总生存率分别为 10.11 ± 1.52 年和 10.18 ± 0.22 年。在 3 种 MB 细胞系中敲低 GLI2 会导致 MTT（3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴盐）测定的细胞数量和活力降低；敲低 GLI1 则没有效果。GLI2 敲低导致细胞数量减少是由于 G0 细胞周期停滞所致；没有诱导细胞凋亡。这些结果表明，针对阳性患者的 Sonic hedgehog 通路可能是 MB 的一种有用的辅助治疗策略。
