Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma

Abstract

Malignant astrocytoma includes anaplastic astrocytoma (grade III) and glioblastoma (grade IV). Among them, glioblastoma is the most common primary brain tumor with dismal responses to all therapeutic modalities. We performed a large-scale, genome-wide microRNA (miRNA) (n ¼ 756) expression profiling of 26 glioblastoma, 13 anaplastic astrocytoma and 7 normal brain samples with an aim to find deregulated miRNA in malignant astrocytoma. We identified several differentially regulated miRNAs between these groups, which could differentiate glioma grades and normal brain as recognized by PCA. More importantly, we identified a most discriminatory 23-miRNA expression signature, by using PAM, which precisely distinguished glioblastoma from anaplastic astrocytoma with an accuracy of 95%. The differential expression pattern of nine miRNAs was further validated by real-time RT-PCR on an independent set of malignant astrocytomas (n ¼ 72) and normal samples (n ¼ 7). Inhibition of two glioblastoma-upregulated miRNAs (miR-21 and miR-23a) and exogenous overexpression of two glioblastoma-downregulated miRNAs (miR-218 and miR-219-5p) resulted in reduced soft agar colony formation but showed varying effects on cell proliferation and chemosensitivity. Thus we have identified the miRNA expression signature for malignant astrocytoma, in particular glioblastoma, and showed the miRNA involvement and their importance in astrocytoma development.

Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor

“… a Lab Data: Genome‐wide expression profiling identifies deregulated miRNAs in malignant astrocytoma (Rao et al ., 2010). …”

“…miRNAs play a crucial role in the maintenance of homeostasis by refining the expression of protein‐coding genes. Glioblastoma or the grade IV astrocytoma is no exception and is significantly influenced by the misregulation of miRNAs (Karsy et al ., 2012; Rao et al ., 2010). There are many studies that have reported the aberrant expression of miRNAs in GBM (Ciafre et al ., 2005; Rao et al ., 2010).…”

“…Glioblastoma or the grade IV astrocytoma is no exception and is significantly influenced by the misregulation of miRNAs (Karsy et al ., 2012; Rao et al ., 2010). There are many studies that have reported the aberrant expression of miRNAs in GBM (Ciafre et al ., 2005; Rao et al ., 2010). miRNAs although do not encode any proteins but they can certainly function as potential oncogenes and tumour suppressors, thereby invoking a paradigm change in the normal functioning of a cell.…”

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

“…1C). Among these miRNAs, miR-146a, miR-182, miR-183, and miR199a-3p are shown to be enriched in diverse cancers, whereas miR-127 and miR-140 are downregulated in gliomas (32,46). In contrast to the unchanged expression of miR-146b, miR146a was significantly induced by EGFR vIII alone or in combination with ablation of Pten (Fig.…”

Apoptosis and the target genes of microRNA-21

“…It is also reported to be up-regulated in hematological malignancies such as leukemia[2], lymphoma[3], and multiple myeloma[4]. miR-21 is overexpressed in glioblastoma[5], osteosarcoma [6], and spermatocytic seminoma[7]. Thus, miR-21 appears to be the only miRNA or the only gene that is found to be overexpressed in all major classes of human cancers derived from epithelial cells, connective tissues, hematopoietic cells, germ cells, or nervous cells, supporting the premise that miR-21 is a ubiquitous Oncogene.…”