MicroRNA Regulation Critical for Development of Pediatric Brain Tumors

MicroRNAs (miRNAs) are a small noncoding family of 19- to 25-nucleotide RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) in a sequence specific manner, inducing translational repression or mRNA degradation, depending on the degree of complementarity between miRNAs and their targets. Many miRNAs are conserved in sequence between distantly related organisms, suggesting that these molecules participate in essential processes. In fact, miRNAs have been shown to be involved in the regulation of gene expression during development, cell proliferation, apoptosis, glucose metabolism, stress resistance, and cancer.

Low-grade gliomas and glioneuronal tumors represent the most frequent primary tumors of the central nervous system in children. Unlike many other types of cancerous tumors, these low-grade pediatric gliomas appear to have few genetic mutations, so the molecular basis for their development has been unclear.

Investigators at Johns Hopkins University (Baltimore, MD, USA) chose to examine a possible role for miRNAs in the development of pediatric gliomas, since miRNAs had been identified as molecular regulators of protein expression/translation that could repress multiple mRNAs concurrently through base pairing, and had an important role in other cancers.

The investigators used the NanoString (Seattle, WA, USA) digital counting system to analyze the expression levels of 800 microRNAs in nine low-grade glial and glioneuronal tumor types.

They reported in the October 14, 2016, online edition of the journal Modern Pathology that a set of 61 microRNAs were differentially expressed in tumors compared with normal brain tissues, and several showed levels varying by tumor type. MicroRNAs miR-4488 and miR-1246 were overexpressed in dysembryoplastic neuroepithelial tumors compared with brain tissue and other tumors, while miR-487b was variably under-expressed in pediatric glioma lines compared with human neural stem cells.

The investigators employed lentiviral vectors to overexpress miR-487b in a pediatric glioma cell line. These modified cells were found to be less cancer-like, forming 30% fewer colonies and had decreased levels of some proteins, such as Nestin (neuroectodermal stem cell marker). Nestin is known to be important in both early development and in cancers.

Senior author Dr. Fausto J.Rodriguez, associate professor of pathology at Johns Hopkins University, said, "Physicians might be able to look at the levels of this and other microRNAs in blood or cerebrospinal fluid to test for the presence of cancer. Researchers might also be able to target microRNAs directly, altering their levels to make cancer cells less likely to form tumors. By gaining a better understanding of the fine genetic differences between cancers and healthy tissues, we can develop better therapeutic or prognostic strategies."

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