Cannabinol Inhibits Cellular Proliferation, Invasion, and Angiogenesis of Neuroblastoma via Novel miR-34a/tRiMetF31/PFKFB3 Axis

Abstract

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 tRNAiMet 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.