miR‐542‐3p exerts tumor suppressive functions in neuroblastoma by downregulating Survivin

Abstract

MicroRNAs (miRNAs) are deregulated in a variety of human cancers, including neuroblastoma, the most common extracranial tumor of childhood. We previously reported a signature of 42 miRNAs to be highly predictive of neuroblastoma outcome. One miRNA in this signature, miR-542, was downregulated in tumors from patients with adverse outcome. Reanalysis of quantitative PCR and next-generation sequencing transcript data revealed that miR-542-5p as well as miR-542-3p expression is inversely correlated with poor prognosis in neuroblastoma patients. We, therefore, analyzed the function of miR-542 in neuroblastoma tumor biology. Ectopic expression of miR-542-3p in neuroblastoma cell lines reduced cell viability and proliferation, induced apoptosis and downregulated Survivin. Survivin expression was also inversely correlated with miR-542-3p expression in primary neuroblastomas. Reporter assays confirmed that miR-542-3p directly targeted Survivin. Downregulating Survivin using siRNA copied the phenotype of miR-542-3p expression in neuroblastoma cell lines, while cDNA-mediated ectopic expression of Survivin partially rescued the phenotype induced by miR-542-3p expression. Treating nude mice bearing neuroblastoma xenografts with miR-542-3p-loaded nanoparticles repressed Survivin expression, decreased cell proliferation and induced apoptosis in the respective xenograft tumors. We conclude that miR-542-3p exerts its tumor suppressive function in neuroblastoma, at least in part, by targeting Survivin. Expression of miR-542-3p could be a promising therapeutic strategy for treating aggressive neuroblastoma.

Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance

“…7, 8 Survivin had been previously shown to be a potential drug target in neuroblastoma. 9, 10, 11, 12, 13 However, survivin had not been investigated as a therapeutic target in the acquired resistance setting in neuroblastoma prior to this study. Our principal findings are that survivin is a promising drug target in p53 wild-type neuroblastoma cells with acquired drug resistance and that YM155 impairs neuroblastoma cell viability in clinically achievable concentrations via survivin depletion.…”

Nanoparticle-mediated inhibition of survivin to overcome drug resistance in cancer therapy

“…A recent study showed that overexpression of miR-214-3p in esophageal squamous cancer cells enhanced sensitivity to cisplatin by directly targeting survivin [106]. Similarly, miR-542-3p, another tumor-suppressive miRNA, could also directly downregulate the expression of survivin [107,108]. Like any other nucleic acid therapeutics, miRNA requires an effective intracellular delivery to realize its potential [109,110].…”

“…Like any other nucleic acid therapeutics, miRNA requires an effective intracellular delivery to realize its potential [109,110]. Intravenous injection of neuroblastoma xenografted nude mice with miR-542-3p-loaded calcium phosphate NPs significantly increased miR-542-3p expression, decreased survivin expression, inhibited cell proliferation and induced apoptosis in xenograft tumors [108] (Fig. 4).…”

“…D) Expression of survivin in neuroblastoma xenograft tumors. Reproduced with permission from[108]. Copyright 2014, John Wiley and Sons.…”

Tumor cell-secreted angiogenin induces angiogenic activity of endothelial cells by suppressing miR-542-3p

“…It has been reported that miR-542-3p is underexpressed in a variety of human cancers such as lung, colon [12], prostate [13], gastric cancer [14], and neuroblastoma [14], which are mediated by C-Src-related signaling pathway [13] and CpG island methylation [15]. Ectopic expression of miR-542-3p inhibits tumor progression through targeting Survivin [16,17], ILK [13], COX-2 [18], AEG-1 [14], and so on. Interestingly, overexpression of miR-542-3p in tumor cells can enhance the protein stability of p53 by targeting its negative regulator MDM2 [12].…”