Abstract
microRNA (miRNA) dysregulation is associated with various types of human cancer by regulating cancer cell survival, proliferation and invasion. Aberrant expression of microRNA-503 (miR-503) has been reported in several cancer profiles. However, potential linkage of miR-503 levels and the underlying regulatory mechanisms in human glioblastoma multiforme (GBM) remain unclear. In the present study, we showed for the first time that the expression of miR-503 was significantly reduced in GBM tissues and cell lines (U251 and U87MG) relative to normal brain tissues. Furthermore, our results demonstrated that overexpression of miR-503 in GBM cell lines not only suppressed cell proliferation through inducing G0/G1 cell cycle arrest and apoptosis, but also inhibited cancer cell migration and tumor invasion. In addition, we identified insulin-like growth factor-1 (IGF-1R) receptor mRNA is a bona fide target of miR-503 by computational analysis followed by luciferase reporter assays. Of note, upregulation of miR-503 in GBM cells suppressed endogenous IGF-1R protein expression. Further mechanistic analysis revealed that forced expression of miR-503 inhibited AKT activation, suggesting the tumor suppressive effect of miR-503 in GBM cells is partially mediated by phosphatidylinositol 3-kinase/AKT signaling. Taken together, the results of the present study demonstrated that miR-503 is a tumor suppressor for GBM and a favorable factor against glioma progression through targeting IGF-1R, thus providing a new evidence-supported prognostic marker for GBM diagnosis.
Highlights
Glioma is the most common intracranial tumor accounting for ~60% of all intracranial tumors [1]
Histograms showed G0/G1 phase arrest and S phase decline in both cell lines transfected with miR-503 mimics. *p
We found that miR-503 was downregulated in glioblastoma multiforme (GBM) tissues and cell lines related to normal brain tissues
Summary
Glioma is the most common intracranial tumor accounting for ~60% of all intracranial tumors [1]. Grade IV tumor refers to glioblastoma multiforme (GBM) that is the most aggressive form of glioma [2]. MiR-181a/b/c were downregulated in GBMs compared to the normal brain tissues. A group of miRNAs including miR-16 and miR-195, which belong to the miR-15/16 family involving miR-15a/b, miR-16, miR-195, miR-424 and miR-497, are downregulated in human glioblastoma cells, and their abnormal expression patterns are associated with the survival rate of GBM patients compared to non-tumorous cells [7,8,9]. MicroRNA-503 (miR‐503) is a member of the miR-15/16 family and it was first reported as a highly elevated miRNA in human retinoblastoma tissues using miRNA microarray analysis [10,11]. The relative expression of miR-503 between GBM and normal brain as well as the function of miR-503 on GBM is unclear
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