Michaelsen Gustavo Lovatto, de Sousa Monteiro Tayrone, Imparato Danilo Oliveira, da Costa João Vitor Almeida, Silva Daniel Rocha, de Souza Iara Dantas, da Ribeiro-Dantas Marcel Câmara, Cabral-Marques Otávio, Sinigaglia Marialva, Dalmolin Rodrigo Juliani Siqueira
Bioinformatics Multidisciplinary Environment-BioME, Digital Metropole Institute, Federal University of Rio Grande do Norte, Natal, 59076-550, RN, Brazil.
Children's Cancer Institute, Porto Alegre, 90620-110, RS, Brazil.
Sci Rep. 2025 May 10;15(1):16310. doi: 10.1038/s41598-025-00763-3.
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for approximately 20% of all childhood brain tumors. Despite recent advances, current treatments like surgery, radiation, and chemotherapy still lead to severe side effects and high morbidity. Limited knowledge exists regarding the regulatory mechanisms behind the MB transcriptional alterations in high-aggressive subgroups like Group 3 and Group 4, hindering the development of targeted therapies. Identifying key transcriptional regulators, known as master regulators (MRs), can elucidate the dysregulated pathways underlying MB progression and uncover potential treatment targets. In this study, we utilize primary MB gene expression samples to infer its regulatory network. Subsequently, we applied the Master Regulator Analysis identifying the transcription factors BHLHE41, RFX4, and NPAS3 as its main transcriptional regulators, showing tumor suppressor features. We also identified eight risk MRs highly associated with patient outcome: four regulators (MYC, REL, ZSCAN5 A, and ZFAT) with activities associated with poor prognosis, and four (PAX6, ARNT2, ZNF157, and HIVEP3) acting antagonistically, being associated with good outcome. Our results offer key insights into the molecular mechanisms driving these tumors and identify novel potential therapeutic targets, addressing the urgent need for more effective and less toxic treatments.
髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤，约占所有儿童脑肿瘤的20%。尽管最近有进展，但目前的治疗方法，如手术、放疗和化疗，仍然会导致严重的副作用和高发病率。对于3组和4组等高侵袭性亚组中MB转录改变背后的调控机制了解有限，这阻碍了靶向治疗的发展。识别关键的转录调节因子，即主调节因子（MRs），可以阐明MB进展背后失调的途径，并揭示潜在的治疗靶点。在本研究中，我们利用原发性MB基因表达样本推断其调控网络。随后，我们应用主调节因子分析，确定转录因子BHLHE41、RFX4和NPAS3为其主要转录调节因子，显示出肿瘤抑制特征。我们还确定了八个与患者预后高度相关的风险MRs：四个调节因子（MYC、REL、ZSCAN5 A和ZFAT）的活性与不良预后相关，另外四个（PAX6、ARNT2、ZNF157和HIVEP3）起拮抗作用，与良好预后相关。我们的结果为驱动这些肿瘤的分子机制提供了关键见解，并确定了新的潜在治疗靶点，满足了对更有效、毒性更小的治疗的迫切需求。
