Wang Bo, Li Dongping, Cherkasova Viktoriia, Gerasymchuk Marta, Narendran Aru, Kovalchuk Igor, Kovalchuk Olga
Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada.
Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada.
Cancers (Basel). 2022 Apr 10;14(8):1908. doi: 10.3390/cancers14081908.
High-risk neuroblastoma is an aggressive pediatric tumor. Despite great advances in neuroblastoma therapy and supportive care protocols, no curative treatment is available for most patients with this disease. Here, we uncover that CBN attenuated the cell proliferation, invasion, and angiogenesis of neuroblastoma cell lines in a dose-dependent manner via the inhibition of the AKT pathway and the upregulation of miR-34a that targets E2F1. Both miR-34a and a 31-nt tRNA fragment (tRiMetF31) derived from miR-34a-guided cleavage were downregulated in 4 examined neuroblastoma cell lines inversely correlated with the levels of its direct target, the PFKFB3 protein. Moreover, ectopic tRiMetF31 suppressed proliferation, migration, and angiogenesis in the studied neuroblastoma cell lines. Conversely, tRiMetF31 knockdown promoted PFKFB3 expression, resulting in enhanced angiogenesis. Our findings reveal a suppressive role of CBN in neuroblastoma tumorigenesis, highlighting a novel and crucial miR-34a tumor suppressor network in CBN's antineuroblastoma actions.
高危神经母细胞瘤是一种侵袭性儿科肿瘤。尽管神经母细胞瘤治疗和支持性护理方案取得了巨大进展，但大多数患有这种疾病的患者仍没有治愈性治疗方法。在此，我们发现CBN通过抑制AKT途径和上调靶向E2F1的miR-34a，以剂量依赖的方式减弱神经母细胞瘤细胞系的细胞增殖、侵袭和血管生成。在4种检测的神经母细胞瘤细胞系中，miR-34a及其源自miR-34a引导切割的31个核苷酸的tRNA片段（tRiMetF31）均下调，与其直接靶点PFKFB3蛋白的水平呈负相关。此外，异位表达的tRiMetF31抑制了所研究的神经母细胞瘤细胞系的增殖、迁移和血管生成。相反，敲低tRiMetF31可促进PFKFB3表达，导致血管生成增强。我们的研究结果揭示了CBN在神经母细胞瘤肿瘤发生中的抑制作用，突出了一个新的关键的miR-34a肿瘤抑制网络在CBN抗神经母细胞瘤作用中的作用。
