Unit of Molecular Genetics of Aging, Department of Ecology and Biology, University of Tuscia, 01100 Viterbo, Italy.
Unit of Molecular Pathology, Department of Experimental Medicine, Section of Terni, University of Perugia, 06100 Perugia, Italy.
Int J Mol Sci. 2021 Sep 17;22(18):10070. doi: 10.3390/ijms221810070.
Neuroblastoma, the most common extra-cranial solid tumor of early childhood, is one of the major therapeutic challenges in child oncology: it is highly heterogenic at a genetic, biological, and clinical level. The high-risk cases have one of the least favorable outcomes amongst pediatric tumors, and the mortality rate is still high, regardless of the use of intensive multimodality therapies. Here, we observed that neuroblastoma cells display an increased expression of Cockayne Syndrome group B (CSB), a pleiotropic protein involved in multiple functions such as DNA repair, transcription, mitochondrial homeostasis, and cell division, and were recently found to confer cell robustness when they are up-regulated. In this study, we demonstrated that RNAi-mediated suppression of CSB drastically impairs tumorigenicity of neuroblastoma cells by hampering their proliferative, clonogenic, and invasive capabilities. In particular, we observed that CSB ablation induces cytokinesis failure, leading to caspases 9 and 3 activation and, subsequently, to massive apoptotic cell death. Worthy of note, a new frontier in cancer treatment, already proved to be successful, is cytokinesis-failure-induced cell death. In this context, CSB ablation seems to be a new and promising anticancer strategy for neuroblastoma therapy.
神经母细胞瘤是儿童期最常见的颅外实体瘤，是儿童肿瘤学中主要的治疗挑战之一：它在遗传、生物学和临床水平上具有高度异质性。高危病例在儿科肿瘤中预后最差之一，且死亡率仍然很高，无论是否使用强化多模式治疗。在这里，我们观察到神经母细胞瘤细胞显示出 Cockayne 综合征组 B（CSB）的表达增加，CSB 是一种多功能蛋白，参与多种功能，如 DNA 修复、转录、线粒体稳态和细胞分裂，并且最近发现当它们上调时可以赋予细胞稳健性。在这项研究中，我们证明了 RNAi 介导的 CSB 抑制通过阻碍神经母细胞瘤细胞的增殖、克隆形成和侵袭能力，极大地损害了其致瘤性。特别是，我们观察到 CSB 缺失诱导胞质分裂失败，导致半胱天冬酶 9 和 3 的激活，随后导致大量细胞凋亡死亡。值得注意的是，癌症治疗的一个新领域，已经被证明是成功的，即胞质分裂失败诱导的细胞死亡。在这种情况下，CSB 缺失似乎是神经母细胞瘤治疗的一种新的有前途的抗癌策略。
