<b>Results:</b> The expression level of miR-34a was decreased (<i>p</i> < .05) while the expression level of HNF4α was increased (<i>p</i> < .05) in paediatric neuroblastoma tissues.
We further found that (1) miR-34a binds the 3'UTR of ADRA2A, (2) the amount of repression is greater when the minor (risk) allele is present, (3) miR-34a in the IMR-32 adrenergic neuroblastoma cell line affects ADRA2A expression, (4) miR-34a and ADRA2A are expressed in tissues known to play a role in pain and stress, (5) following forced swim stress exposure, rat peripheral nerve tissue expression changes are consistent with miR-34a regulation of ADRA2A.
Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model.
Over expression of miR-34a in both NB1691luc and SK-N-ASluc neuroblastoma cell lines led to a significant decrease in cell number relative to premiR-negative control treated cells over a 72 hour period.
To better understand the biological pathways involved in miR-34a action, a parallel global protein and mRNA expression profiling on miR-34a treated neuroblastoma cells (IMR32) was performed using isotope-coded affinity tags (ICAT) and Affymetrix U133plus2 microarray, respectively.
More recently, the dysregulation of some miRNAs, including the miR-17-5p-92 cluster and miR-34a, has been implicated in the pathobiology of neuroblastoma.
Expression of miR-34a was also decreased in primary tumors (n = 54) with 1p36 deletion (P = 0.009), but no mutations were discovered in resequencing of the miR-34a locus in 30 neuroblastoma cell lines.
For example, miR-15 and miR-16 induce apoptosis by targeting Bcl2. miRNAs from the miR-17-92 cluster modulate tumor formation and function as oncogenes by influencing the translation of E2F1 mRNA. miR-21 modulates gemcitabine-induced apoptosis by phosphatase and tensin homolog deleted on chromosome 10-dependent activation of PI 3-kinase signaling. miR-34a acts as a suppressor of neuroblastoma tumorigenesis by targeting the mRNA encoding E2F3 and reducing E2F3 protein levels.