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

by Selleckchem | Mar 30 2023

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.

Comments：

The purpose of this study was to identify dysregulated miRNAs in meningioma and investigate miRNA-associated pathways that could be targeted for therapeutic interventions. The researchers performed small RNA sequencing on meningioma tumor samples to study grade-dependent changes in microRNA expression. They found that meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, which was associated with high mRNA and protein expression of its host gene IGF-2.

The researchers then conducted experiments to study the effects of inhibiting or enhancing the miR-483/IGF-2 pathway on meningioma cell growth. They found that 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.

The researchers also tested the effects of blocking the IGF-2 receptor (IGF1R) with small molecule tyrosine kinase inhibitors on cultured meningioma tumor-derived cells. They found that this resulted in rapid loss of viability of the cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The researchers predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma, based on the observed IGF1R-inhibitory IC50 for GSK1838705A and ceritinib in cell-based assays along with the available pharmacokinetics data.

In conclusion, the researchers found that meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a feasible meningioma treatment target.