MiR-326: Role and significance in brain cancers

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that act as critical regulators of gene expression by repressing mRNA translation. The role of miRNAs in cell physiology spans from cell cycle control to cell proliferation and differentiation, both during development and in adult tissues. Accordingly, dysregulated expression of miRNAs has been reported in several diseases, including cancer, where miRNAs can act as oncogenes or oncosuppressors. Of note, miRNA signatures are also under investigation for classification, diagnosis, and prognosis of cancer patients. Brain tumours are primarily associated with poor prognosis and high mortality, highlighting an urgent need for novel diagnostic, prognostic, and therapeutic tools. Among miRNAs investigated in brain tumours, miR-326 has been shown to act as a tumour suppressor in adult and paediatric brain cancers. In this review, we describe the role of miR-326 in malignant as well as benign cancers originating from brain tissue. In addition, since miR-326 expression can be regulated by other non-coding RNA species, adding a further layer of regulation in the cancer-promoting axis, we discuss this miRNA's role in targeted therapy for brain cancers.

Keywords: ARRB1; Circular RNAs (circRNAs); Gliomas; Long non-coding RNAs (lncRNAs); Medulloblastoma; MiR-326; Pituitary adenomas.

Fig. 1

MiR-326 resides in the same intron of the β-arrestin1 gene and shares the same regulatory regions. In 2008, Ferretti et al. demonstrated that miR-326 acts targeting the Hedgehog (HH) pathway to induce cerebellar granule cell precursors differentiation [22]. Two years later, Parathath et al. described a model in which β-arrestin1, after activation and nuclear translocation, induced the transcription of p27 driving GCPs exit from cell cycle [33]. Then, in 2017, Po et al. described an epigenetic silencing of the complex β-arrestin1/miR-326 that inhibit their expression in cerebellar neural stem cells maintaining stemness features [34]. Created with BioRender.

Fig. 2

The loss of miR-326 expression has been observed in pituitary GH-adenoma, adult GBM, and pediatric MB brain cancer cells. Consequently, cancer cells have been shown to express miR-326 verified targets abnormally. MiR-326 expression and activity can be suppressed by overrepresented molecules (PI3K/AKT axis) and by molecular sponges, such as non-coding RNAs (circRNAs and lncRNAs). Loss of miR-326 expression and thus its inhibitory activity on mRNA targets contribute to increased stemness, survival, migratory capabilities, and even metabolic adaptation of cancer cells. Created with BioRender.

Fig. 3

MiR-326 and β-arrestin1 expression in brain cancer cells may be restored by different approaches. MiR-326 levels could be increased by delivering mimics or synthetic double stranded-RNA embedded in NPs. Through the RISC complex, the suppression of miR-326 targets could be achieved. β-arrestin1 and miR-326 locus might be transcriptionally reactivated by unlocking the hypermethylation sites. In the end, the repression of circRNA and/or lncRNA sponging activity could contribute to increasing the levels of miR-326. These strategies might help to recover the biological activity of miR-326, thus decreasing the stemness, survival, migratory capabilities, and even metabolism of cancer cells. Created with BioRender.