Synthetic miR-21 decoy circularized by tRNA splicing mechanism inhibited tumorigenesis in glioblastoma in vitro and in vivo models

Hadi Bayat; Mohammad Hossein Pourgholami; Saeid Rahmani; Safura Pournajaf; Seyed Javad Mowla

doi:10.1016/j.omtn.2023.04.001

Synthetic miR-21 decoy circularized by tRNA splicing mechanism inhibited tumorigenesis in glioblastoma in vitro and in vivo models

Mol Ther Nucleic Acids. 2023 Apr 6:32:432-444. doi: 10.1016/j.omtn.2023.04.001. eCollection 2023 Jun 13.

Authors

Hadi Bayat¹, Mohammad Hossein Pourgholami², Saeid Rahmani³, Safura Pournajaf², Seyed Javad Mowla¹

Affiliations

¹ Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14115-111, Iran.
² Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14115-111, Iran.
³ School of Computer Science, Institute for Research in Fundamental Sciences (IPM), Tehran 19538-33511, Iran.

Abstract

Glioblastoma multiforme (GBM) is the deadliest primary central nervous system tumor. miRNAs (miRs), a class of non-coding RNAs, are considered pivotal post-transcriptional regulators of cell signaling pathways. miR-21 is a reliable oncogene that promotes tumorigenesis of cancer cells. We first performed an in silico analysis on 10 microarray datasets retrieved from TCGA and GEO databases to elucidate top differentially expressed miRs. Furthermore, we generated a circular miR-21 decoy, CM21D, using the tRNA-splicing mechanism in GBM cell models, U87 and C6. The inhibitory efficacy of CM21D with that of a linear form, LM21D, was compared under in vitro conditions and an intracranial C6 rat glioblastoma model. miR-21 significantly overexpressed in GBM samples and confirmed in GBM cell models using qRT-PCR. CM21D was more efficient than LM21D at inducing apoptosis, inhibiting cell proliferation and migration, and interrupting the cell cycle by restoring the expression of miR-21 target genes at RNA and protein levels. Moreover, CM21D suppressed tumor growth more effectively than LM21D in the C6-rat GBM model (p < 0.001). Our findings validate miR-21 as a promising therapeutic target for GBM. The introduced CM21D by sponging miR-21 reduced tumorigenesis of GBM and can be considered a potential RNA-base therapy to inhibit cancers.

Keywords: MT: Oligonucleotides: Therapies and Applications; circular RNA; glioblastoma; miR-21; miRNA decoy; tRNA splicing.