Interdisciplinary Brain Research Centre, Faculty of Medicine, J. N. Medical College, Aligarh Muslim University, Aligarh, 202002, India.
Department of Neurosurgery, J. N. Medical College, Aligarh Muslim University, Aligarh, 202002, India.
Mol Biol Rep. 2024 Oct 26;51(1):1096. doi: 10.1007/s11033-024-10026-5.
Medulloblastoma is a pediatric malignant brain tumor associated with an aberrantly activated Shh pathway. The Shh pathway acts via downstream effector molecules, including Pax6 and Nkx2.2. Transcription factor Nkx2.2 plays crucial roles during early embryonic patterning and development. In this study, we aimed to determine the role of transcription factor Nkx2.2 in medulloblastoma development.
Here, whole transcriptome levels and suppressive effect of transcription factor Nkx2.2 on Pax6 were assessed using one normal human brain and three surgically removed medulloblastoma samples. Additionally, protein levels of Shh, Gli1, Pax6, and Nkx2.2 and co-expression patterns of Pax6 and Nkx2.2 were assessed in 14 medulloblastoma samples. Quantitative reverse transcription-polymerase chain reaction revealed the suppressive effect of Nkx2.2 on Pax6. D283 cells were treated with the Shh pathway activator, SAG, and Gli1 inhibitor, GANT61, which revealed Pax6-Nkx2.2 regulation. Increased cell proliferation was observed in D283 cells transfected with Nkx2.2 small interfering RNA. Moreover, mRNA expression levels of Shh, Pax6, Nkx2.2, and Gli1 were assessed in Daoy cells transfected with Gli1 and Nkx2.2 small interfering RNAs using quantitative reverse transcription-polymerase chain reaction. Pax6 levels were increased in Nkx2.2 siRNA-transfected cells.
Aberrantly activated Shh pathway leads to the ectopic expression of Pax6 in granular cells, inducing medulloblastoma development. Moreover, Nkx2.2 transcription factor acts as a suppressor of Pax6 during medulloblastoma development and maintenance. Overall, this study provides novel insights for the development of effective therapeutic strategies and suggests potential targets for medulloblastoma.
成神经管细胞瘤是一种与异常激活的 Shh 通路相关的小儿恶性脑肿瘤。Shh 通路通过下游效应分子，包括 Pax6 和 Nkx2.2 起作用。转录因子 Nkx2.2 在早期胚胎模式形成和发育中发挥关键作用。在这项研究中，我们旨在确定转录因子 Nkx2.2 在成神经管细胞瘤发展中的作用。
在这里，使用一个正常人脑和三个手术切除的成神经管细胞瘤样本评估了转录因子 Nkx2.2 的全转录组水平和对 Pax6 的抑制作用。此外，在 14 个成神经管细胞瘤样本中评估了 Shh、Gli1、Pax6 和 Nkx2.2 的蛋白水平以及 Pax6 和 Nkx2.2 的共表达模式。定量逆转录-聚合酶链反应显示 Nkx2.2 对 Pax6 具有抑制作用。用 Shh 通路激活剂 SAG 和 Gli1 抑制剂 GANT61 处理 D283 细胞，揭示了 Pax6-Nkx2.2 的调节。转染 Nkx2.2 小干扰 RNA 的 D283 细胞观察到细胞增殖增加。此外，用 Gli1 和 Nkx2.2 小干扰 RNA 转染 Daoy 细胞后，使用定量逆转录-聚合酶链反应评估了 Shh、Pax6、Nkx2.2 和 Gli1 的 mRNA 表达水平。在 Nkx2.2 siRNA 转染的细胞中，Pax6 水平升高。
异常激活的 Shh 通路导致颗粒细胞中 Pax6 的异位表达，诱导成神经管细胞瘤的发展。此外，Nkx2.2 转录因子在成神经管细胞瘤的发生和维持过程中作为 Pax6 的抑制剂。总的来说，这项研究为开发有效的治疗策略提供了新的见解，并为成神经管细胞瘤提供了潜在的治疗靶点。
