High-throughput microRNA profiling of pediatric high-grade gliomas

Abstract

BackgroundHigh-grade gliomas (HGGs) account for 15% of all pediatric brain tumors and are a leading cause of cancer-related mortality and morbidity. Pediatric HGGs (pHGGs) are histologically indistinguishable from their counterpart in adulthood. However, recent investigations indicate that differences occur at the molecular level, thus suggesting that the molecular path to gliomagenesis in childhood is distinct from that of adults. MicroRNAs (miRNAs) have been identified as key molecules in gene expression regulation, both in development and in cancer. miRNAs have been investigated in adult high-grade gliomas (aHGGs), but scant information is available for pHGGs.MethodsWe explored the differences in microRNAs between pHGG and aHGG, in both fresh-frozen and paraffin-embedded tissue, by high-throughput miRNA profiling. We also evaluated the biological effects of miR-17-92 cluster silencing on a pHGG cell line.ResultsComparison of miRNA expression patterns in formalin versus frozen specimens resulted in high correlation between both types of samples. The analysis of miRNA profiling revealed a specific microRNA pattern in pHGG with an overexpression and a proliferative role of the miR-17-92 cluster. Moreover, we highlighted a possible quenching function of miR-17-92 cluster on its target gene PTEN, together with an activation of tumorigenic signaling such as sonic hedgehog in pHGG.ConclusionsOur results suggest that microRNA profiling represents a tool to distinguishing pediatric from adult HGG and that miR-17-92 cluster sustains pHGG.

Genome‐wide small noncoding RNA profiling of pediatric high‐grade gliomas reveals deregulation of several miRNAs, identifies downregulation of snoRNA cluster HBII‐52 and delineates H3F3A and TP53 mutant‐specific miRNAs and snoRNAs

“…The role of miRNAs has been widely studied in multiple aspects of adult GBM biology, showing their profound involvement in the regulation of gene expression involving vital cellular processes such as angiogenesis, metabolic reprogramming and stem cell behavior . However, in this perspective, pediatric HGG is an understudied disease compared to their adult counterparts with only two studies on restricted number of miRNAs in pediatric HGGs . Here, we present, for the first time, genome‐wide miRNA as well as snoRNA expression signature in pediatric HGGs.…”

“…It is potentially oncogenic in nature and regulates tumor development and maintenance. Miele et al . suggested that in pediatric HGGs, miR‐17/92 promotes cell proliferation through a possible quenching of tumor suppressor gene PTEN and activation of sonic hedgehog signaling.…”

“…Till date, the involvement of miRNAs has only been partially explored. There is one report by Birks et al 18 in 2011, based on 470 miRNAs in four pediatric GBM cases and another study by Miele et al 19 2013 on only 754 miRNAs. The observations of these studies are rather inadequate in the perspective of recent miRbase update with 2,000 miRNAs and miRNA-based findings in adult GBMs.…”

“…There is one report by Birks et al . in 2011, based on 470 miRNAs in four pediatric GBM cases and another study by Miele et al . 2013 on only 754 miRNAs.…”

Beyond circulating microRNA biomarkers: Urinary microRNAs in ovarian and breast cancer

“…This can occur via a perfect complimentary binding of the miRNA to the target mRNA (endonucleolytic cleavage of the mRNA) or by an imperfect complimentary binding to the target mRNA (translation repression). 32 Due to their cell cycle interference, miRNAs are involved either as oncogenes or as oncosuppressors in the pathogenesis of a huge variety of human cancers such as lung cancer, 33,34 prostate cancer, 35 colorectal cancer, 36,37 leukemia, [38][39][40] gliomas 41 and medulloblastoma, 42 diffuse large B-cell lymphoma, 43 hepatocellular carcinoma (HCC), 44 gastric cancer, 45,46 osteosarcoma, 47 renal cell carcinoma, 48 BC, 49 and OC. 50 Particularly, their presence in the blood has been shown to be associated with histology, clinical stage, survival, and oncogenic expression in OC and BC.…”