Identification and Functional Characterization of microRNAs Involved in the Malignant Progression of Gliomas

Abstract

Diffuse astrocytoma of World Health Organization (WHO) grade II has an inherent tendency to spontaneously progress to anaplastic astrocytoma WHO grade III or secondary glioblastoma WHO grade IV. We explored the role of microRNAs (miRNAs) in glioma progression by investigating the expression profiles of 157 miRNAs in four patients with primary WHO grade II gliomas that spontaneously progressed to WHO grade IV secondary glioblastomas. Thereby, we identified 12 miRNAs (miR-9, miR-15a, miR-16, miR-17, miR-19a, miR-20a, miR-21, miR-25, miR-28, miR-130b, miR-140 and miR-210) showing increased expression, and two miRNAs (miR-184 and miR-328) showing reduced expression upon progression. Validation experiments on independent series of primary low-grade and secondary high-grade astrocytomas confirmed miR-17 and miR-184 as promising candidates, which were selected for functional analyses. These studies revealed miRNAspecific influences on the viability, proliferation, apoptosis and invasive growth properties of A172 and T98G glioma cells in vitro. Using mRNA and protein expression profiling, we identified distinct sets of transcripts and proteins that were differentially expressed after inhibition of miR-17 or overexpression of miR-184 in glioma cells. Taken together, our results support an important role of altered miRNA expression in gliomas, and suggest miR-17 and miR-184 as interesting candidates contributing to glioma progression.

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…For example, miR‐9 is expressed at high levels in neural tissues and is essential for the development of the brain (Delaloy et al ., 2010; Uchida, 2010). miR‐9 plays a critical role in regulating the proliferation of neural progenitors and, not surprisingly, has been implicated in the development of different types of brain tumour, such as medulloblastoma and glioblastoma (Ferretti et al ., 2009; Malzkorn et al ., 2010). Several miR‐9 target genes have been described that might play a role in this context.…”

MiR-135a functions as a selective killer of malignant glioma

“…Independent research groups have reported significant miRNA alteration in glioma by profiling (Gaur et al, 2007;Malzkorn et al, 2010). Among these aberrant miRNAs in malignant glioma, miR-124 and miR-128 are better characterized.…”

The emerging role of miR‐19 in glioma

“…MiR‐19 is confirmed to participate in the process of glioma recurrence. A research report has demonstrated that miR‐19 is progression‐associated up‐regulation in patients who has been operated as WHO grade II originally and spontaneously progress to WHO grade IV secondary glioblastoma 26. This indicates that miR‐19 plays an important role in glioma progression.…”