Abstract
Background Increased levels of circRNAs have been identified in a variety of cancers. However, the specific functions and mechanisms of circRNAs in neuroblastoma (NB) have not been fully explored. Methods The levels of hsa_circ_0045997, hsa_circ_0080307, hsa_circ_0013401, hsa_circ_0077578, and microRNA-195 were confirmed by RT-qPCR in NB. Gain- and loss-of-function assays and rescue experiments were conducted to determine the influence of hsa_circ_0013401, miR-195, and P21-activated kinase 2 (PAK2) on the proliferation, apoptosis, autophagy, migration, and invasion of NB cells. Regulatory gene targets were validated by the luciferase assay. A xenograft mouse model was used to determine the in vivo effects of hsa_circ_0013401. Results hsa_circ_0013401 was highly expressed, miR-195 was lowly expressed, and there was a negative correlation between hsa_circ_0013401 and miR-195 in NB. The inhibitory effects of hsa_circ_0013401 knockdown suppressed the proliferation, migration, and invasion and induced the apoptosis and autophagy of NB cells by targeting miR-195 to downregulate PAK2 expression. Luciferase reporter assays showed that miR-195 was a direct target of hsa_circ_0013401, and PAK2 was the downstream target gene of miR-195. In vivo studies showed that hsa_circ_0013401 promotes tumor formation. Conclusions hsa_circ_0013401 induced NB progression through miR-195 to enhance PAK2. Therefore, we might highlight a novel regulatory axis (hsa_circ_0013401/miR-195/PAK2) in NB.
Highlights
Neuroblastoma (NB) is a malignant tumor commonly discovered in the peripheral nervous system of infants [1]
We further demonstrated that an miR-195 inhibitor could reverse the inhibition of cell proliferation, migration, and invasion and induction of cell apoptosis mediated by circ_0013401 knockdown in NB cells
We further demonstrated that P21-activated kinase 2 (PAK2) was significantly upregulated in NB and that PAK2 expression could be significantly reduced by miR-195 and elevated by circ_0013401 overexpression in NB
Summary
Neuroblastoma (NB) is a malignant tumor commonly discovered in the peripheral nervous system of infants [1]. There is an urgent need to identify specific molecules that can be exploited in targeted therapy regimens for NB patients. Gainand loss-of-function assays and rescue experiments were conducted to determine the influence of hsa_circ_0013401, miR195, and P21-activated kinase 2 (PAK2) on the proliferation, apoptosis, autophagy, migration, and invasion of NB cells. The inhibitory effects of hsa_circ_0013401 knockdown suppressed the proliferation, migration, and invasion and induced the apoptosis and autophagy of NB cells by targeting miR-195 to downregulate PAK2 expression. Luciferase reporter assays showed that miR-195 was a direct target of hsa_ circ_0013401, and PAK2 was the downstream target gene of miR-195. In vivo studies showed that hsa_circ_0013401 promotes tumor formation. Hsa_circ_0013401 induced NB progression through miR-195 to enhance PAK2. We might highlight a novel regulatory axis (hsa_circ_0013401/miR-195/PAK2) in NB
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