Distal-less homeobox 5 transactivated by MYCN contributes to progression of neuroblastoma through AKT signaling pathway

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Neuroblastoma is one of the highest incidence solid tumors of childhood. Therapy for neuroblastoma with MYCN proto-oncogene (MYCN) amplification is of great challenge, due to its aggressive invasion and chemoresistance. In our study, differentially expressed genes (DEGs) between MYCN-amplified and non-amplified neuroblastoma tissues were analyzed using "limma" R package. Then, DEGs were screened by silencing or enhancing expression of MYCN in neuroblastoma cells, and distal-less homeobox 5 (DLX5) was identified to be the downstream target gene. The positive correlation between DLX5 and MYCN expression was confirmed in neuroblastoma tissues and cell lines. Overall survival analysis suggested that high expression of DLX5 predicted poor clinical outcome.Then, DLX5 was demonstrated to promote proliferation and migration of neuroblastoma. Gene set enrichment analysis revealed that base excision repair and nucleotide excision repair processes were enriched in samples with DLX5 high expression. Thus, the half-maximal inhibitory concentration was measured and cisplatin treatment assay was carried out. The results revealed DLX5 promoted cisplatin chemoresistance of neuroblastoma. To explore the mechanism, mRNA sequencing was conducted and AKT signaling was suggested to be the mainly regulatory pathway, which was further verified in cells and tumor tissues. Then, we proved that heart and neural crest derivatives expressed 2, paired like homeobox 2B, GATA binding protein 3, and MYCN coregulated the expression of DLX5 at the transcriptional level, and identified the direct binding site of MYCN on DLX5 promoter. Finally, we demonstrated that DLX5 which was transcriptionally activated by MYCN, promoted growth, metastasis and chemoresistance of neuroblastoma through enhanced AKT phosphorylation. The findings in our study provided new insight for progression and chemoresistance of neuroblastoma.

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