Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA.
Centro de Oncologia Molecular, Hospital Sírio-Libanês, Sao Paulo 01308-060, Brazil.
Cells. 2021 Dec 25;11(1):56. doi: 10.3390/cells11010056.
Medulloblastoma is the most common malignant brain tumor in children. Treatment with surgery, irradiation, and chemotherapy has improved survival in recent years, but patients are frequently left with devastating neurocognitive and other sequelae. Patients in molecular subgroups 3 and 4 still experience a high mortality rate. To identify new pathways contributing to medulloblastoma development and create new routes for therapy, we have been studying oncogenic RNA-binding proteins. We defined Musashi1 (Msi1) as one of the main drivers of medulloblastoma development. The high expression of Msi1 is prevalent in Group 4 and correlates with poor prognosis while its knockdown disrupted cancer-relevant phenotypes. Genomic analyses (RNA-seq and RIP-seq) indicated that cell cycle and division are the main biological categories regulated by Msi1 in Group 4 medulloblastoma. The most prominent Msi1 targets include CDK2, CDK6, CCND1, CDKN2A, and CCNA1. The inhibition of Msi1 with luteolin affected the growth of CHLA-01 and CHLA-01R Group 4 medulloblastoma cells and a synergistic effect was observed when luteolin and the mitosis inhibitor, vincristine, were combined. These findings indicate that a combined therapeutic strategy (Msi1 + cell cycle/division inhibitors) could work as an alternative to treat Group 4 medulloblastoma.
髓母细胞瘤是儿童中最常见的恶性脑肿瘤。近年来，通过手术、放疗和化疗的综合治疗，患者的生存率有所提高，但常常会留下严重的神经认知和其他后遗症。分子亚组 3 和 4 的患者仍然死亡率较高。为了确定新的通路导致髓母细胞瘤的发展，并为治疗创造新途径，我们一直在研究致癌 RNA 结合蛋白。我们将 Musashi1（Msi1）定义为髓母细胞瘤发展的主要驱动因素之一。高表达 Msi1 普遍存在于 4 组中，与预后不良相关，而其敲低则破坏了与癌症相关的表型。基因组分析（RNA-seq 和 RIP-seq）表明，细胞周期和分裂是 Msi1 在 4 组髓母细胞瘤中主要调节的生物学类别。最显著的 Msi1 靶标包括 CDK2、CDK6、CCND1、CDKN2A 和 CCNA1。用 luteolin 抑制 Msi1 影响 CHLA-01 和 CHLA-01R 4 组髓母细胞瘤细胞的生长，当 luteolin 和有丝分裂抑制剂长春新碱联合使用时，观察到协同作用。这些发现表明，联合治疗策略（Msi1+细胞周期/分裂抑制剂）可能是治疗 4 组髓母细胞瘤的一种替代方法。
