Inhibition of the epigenetically activated miR-483-5p/IGF-2 pathway results in rapid loss of meningioma tumor cell viability

Abstract

Purpose Meningioma is the most common primary central nervous system tumor often causing serious complications, and presently no medical treatment is available. The goal of this study was to discover miRNAs dysregulated in meningioma, and explore miRNA-associated pathways amenable for therapeutic interventions. Methods Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells. Results Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma. Conclusion Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a feasible meningioma treatment target.

MicroRNAs in meningiomas: Potential biomarkers and therapeutic targets

“…Another study found high and grade-dependent expression of miR-483–5p in meningioma tumor samples, which correlated with increased mRNA and protein levels of its host gene IGF-2 [ 58 ]. Inhibition of miR-483–5p demonstrated decreased growth of cultured meningioma cells, whereas miR-483 mimicked increased cell proliferation.…”

“…Importantly, blockade of the IGF-2 receptor (IGF1R) tyrosine kinase inhibitor with a small molecule inhibitor resulted in a rapid loss of viability of cultured meningioma cells. The results showed that IGF-2 autocrine feedback is critical for the survival and growth of meningioma tumor cells [ 58 ]. This study highlights the critical dependence of meningioma cell growth on the autocrine miR-483/IGF-2 stimulation pathway.…”

“…Notably, the IGF-2 pathway is emerging as a promising and feasible therapeutic target for the treatment of meningioma. Inhibition of miR-483–5p, anti -IGF-2 neutralizing antibodies, and small molecule tyrosine kinase inhibitors targeting IGF1R have demonstrated efficacy in limiting meningioma cell proliferation in vitro [ 58 ]. The observed inhibitory effects of GSK1838705 A and ceritinib on IGF1R, combined with pharmacokinetic data, suggest potential in vivo applications as novel treatments for meningioma.…”