Department of Cell Biochemistry, Faculty of Biotechnology, University of Rzeszow, Poland.
Division of Pediatric Hematology/Oncology, University Hospital, Bern, Switzerland; Department of Emergency Medicine, University Hospital, Bern, Switzerland.
Redox Biol. 2019 Jun;24:101163. doi: 10.1016/j.redox.2019.101163. Epub 2019 Mar 13.
Medulloblastoma (MB) is a common and highly aggressive pediatric brain tumor of a heterogeneous nature. According to transcriptome-based profiling, four molecular subgroups of MB have been revealed, namely WNT, SHH, Group 3 and Group 4. High MYC mRNA expression and MYC gene amplification in MB have been considered as indicators of poor prognosis. However, the role of c-Myc in MB biology is still not well established. In the present study, the effects of c-Myc activation in UW228-MycER MB cell line were investigated using 4-hydroxytamoxifen (4-OHT) induction system. Upon 4-OHT stimulation, an increase in metabolic activity, large-cell/anaplastic (LC/A) phenotype and oxidative stress-mediated DNA damage were observed. However, 53BP1 foci were not implicated in DNA damage response. Instead, cofilin nuclear translocation, changes in F-actin cytoskeleton and the levels of cytoskeletal proteins were shown. Moreover, the telomere length was found to be unaffected that may be associated with the upregulation of TRF proteins. Transcription of nascent RNA (synthesis of new rRNA) and the expression of RNA polymerase I-specific transcription initiation factor RRN3/TIF-IA were also elevated. Moreover, increased levels of DNMT2, a modulator of stress responses, were observed. A small fraction of cells responded differently as oncogene-induced senescence was also noticed. We postulate that c-Myc-mediated modulation of genetic stability of MB cells may trigger cellular heterogeneity and affect adaptive responses to changing environment.
髓母细胞瘤（MB）是一种常见且高度侵袭性的儿童脑肿瘤，具有异质性。根据基于转录组的分析，已经揭示了 MB 的四个分子亚群，即 WNT、SHH、Group 3 和 Group 4。MB 中高 MYC mRNA 表达和 MYC 基因扩增被认为是预后不良的指标。然而，c-Myc 在 MB 生物学中的作用尚未得到很好的确定。在本研究中，使用 4-羟基他莫昔芬（4-OHT）诱导系统研究了 UW228-MycER MB 细胞系中 c-Myc 激活的影响。在 4-OHT 刺激下，观察到代谢活性增加、大细胞/间变性（LC/A）表型和氧化应激介导的 DNA 损伤。然而，53BP1 焦点并未涉及 DNA 损伤反应。相反，发现了纽蛋白核转位、F-肌动蛋白细胞骨架的变化以及细胞骨架蛋白的水平。此外，端粒长度未受影响，这可能与 TRF 蛋白的上调有关。新生 RNA 的转录（新 rRNA 的合成）和 RNA 聚合酶 I 特异性转录起始因子 RRN3/TIF-IA 的表达也增加了。此外，还观察到应激反应调节剂 DNMT2 的水平升高。一小部分细胞反应不同，因为还注意到癌基因诱导的衰老。我们假设 c-Myc 介导的 MB 细胞遗传稳定性的调节可能触发细胞异质性，并影响对不断变化的环境的适应性反应。
