microRNA-221 Enhances MYCN via Targeting Nemo-like Kinase and Functions as an Oncogene Related to Poor Prognosis in Neuroblastoma

Abstract

Purpose: MYCN is one of the most well-characterized genetic markers of neuroblastoma. However, the mechanisms as to how MYCN mediate neuroblastoma tumorigenesis are not fully clear. Increasing evidence has confirmed that the dysregulation of miRNAs is involved in MYCN-mediated neuroblastoma tumorigenesis, supporting their potential as therapeutic targets for neuroblastoma. Although miR-221 has been reported as one of the upregulated miRNAs, the interplay between miR-221 and MYCN-mediated neuroblastoma progression remains largely elusive.Experimental Design: The expression of miR-221 in the formalin-fixed, paraffin-embedded tissues from 31 confirmed patients with neuroblastoma was detected by locked nucleic acid-in situ hybridization and qRT-PCR. The correlation between miR-221 expression and clinical features in patients with neuroblastoma was assessed. The mechanisms as to how miR-221 regulate MYCN in neuroblastoma were addressed. The effect of miR-221 on cellular proliferation in neuroblastoma was determined both in vitro and in vivo.Results: miR-221 was significantly upregulated in neuroblastoma tumor cells and tissues that overexpress MYCN, and high expression of miR-221 was positively associated with poor survival in patients with neuroblastoma. Nemo-like kinase (NLK) as a direct target of miR-221 in neuroblastoma was verified. In addition, overexpression of miR-221 decreased LEF1 phosphorylation but increased the expression of MYCN via targeting of NLK and further regulated cell cycle, particularly in S-phase, promoting the growth of neuroblastoma cells.Conclusions: This study provides a novel insight for miR-221 in the control of neuroblastoma cell proliferation and tumorigenesis, suggesting potentials of miR-221 as a prognosis marker and therapeutic target for patients with MYCN overexpressing neuroblastoma.

In silico discovery of a FOXM1 driven embryonal signaling pathway in therapy resistant neuroblastoma tumors

“…From these observations we anticipated that miRNAs could act as a proxy to capture stem cell features in neuroblastoma cells. Indeed, it has already been shown that miRNAs play important roles in neuroblastoma tumor formation and progression 15 , 16 . The let-7 cluster, previously described as crucial to be downregulated for maintaining pluripotency in stem cells 17 , is frequently lost in neuroblastoma, inversely associated with MYCN amplification status and independently correlated with poor prognosis 18 .…”

SNHG7 Facilitates Glioblastoma Progression by Functioning as a Molecular Sponge for MicroRNA-449b-5p and Thereby Increasing MYCN Expression

“… 24 Through enhancing MYCN, miR-221 is considered as an oncogene linked with unfavorable prognosis in neuroblastoma. 40 It has also been reported that highly MYCN expression in neural stem cells of the developing mouse could lead to the development of GBM. 41 Moreover, MYCN can be targeted and negatively regulated by miR-34a in GBM.…”

MicroRNAs as Potential Biomarkers for Chemoresistance in Adenocarcinomas of the Esophagogastric Junction

“…Nevertheless, the function and effects of these miRNAs as stated in the literature might give some clues as to what the underlying mechanisms might be: for hsa-let-7f-5p, a proangiogenic effect has been reported; thus, overexpression might contribute to tumor progression via tumor neoangiogenesis [38][39][40]. For hsa-miRNA-221-3p, cell cycle regulation has been reported as a key mechanism in tumor progression; in addition, in cervical cancer, increased expression levels are associated with epithelialmesenchymal transition, migration, and invasion by targeting TWIST2 [41,42]. For human glioblastomas, cervical and colon carcinoma cells downregulation of PTEN and activation of Akt and STAT3-mediated by increased levels of hsa-miRNA-221-3p-have been shown as key players in tumor cell survival and radio-and chemoresistance [43][44][45][46].…”