IJMS, Vol. 26, Pages 8263: In Silico Identification of circPIM1/miR-16-5p/miR-195-5p/PIM1 Feed-Forward Loop in Recurrent Grade 2 Meningioma

International Journal of Molecular Sciences doi: 10.3390/ijms26178263

Authors:
Giuseppe Sotera
Carla Forte
Daniele Giuseppe D’Urso
Domenica Reina
Noemi Zuccaro
Andrea Giuseppe Toscano
Angela Caponnetto
Cristina Barbagallo
Giuseppe Broggi
Francesco Certo
Marco Ragusa
Rosario Caltabiano
Cinzia Di Pietro
Giuseppe Maria Vincenzo Barbagallo
Michele Purrello
Davide Barbagallo

In bulk meningioma (MNG) tumors, a biomarker based on the expression of 34 transcripts (34HR-MNG) has recently been described to be able to predict their outcome, including recurrence. To better study the molecular mechanisms regulating the expression of the 34HR-MNG transcripts and predict their functional involvement in MNG recurrence, we built a competitive endogenous RNA (ceRNA) network through an in silico approach. MiRNAs targeting 34HR-MNG transcripts and corresponding sponging circRNAs were retrieved through MiRTarbase and ENCORI databases, respectively. The expression of candidate circRNA host genes belonging to the 34HR-MNG transcripts was correlated with specific molecular and clinical features of 89 and 20 WHO grade 1 and 2 MNGs, respectively, by querying the RNA-seq dataset GSE189672. The expression of candidate circRNAs and their host gene was validated through qRT-PCR. Among the 34HR-MNG transcripts, the Pim-1 proto-oncogene, serine/threonine kinase (PIM1) was significantly upregulated in (i) WHO grade 2 vs. grade 1 and (ii) recurrent vs. not recurrent WHO grade 2 MNGs. PIM1 expression positively and negatively correlated with that of Ki-67 and NF2, respectively, in recurrent WHO grade 2 MNGs. CircRNAs 0076215 and 0076216, both generated from the PIM1 host gene, were predicted to sponge miRNAs 16-5p and 195-5p, two tumor suppressors in MNG, in turn targeting PIM1. The expression of circRNAs 0076215 and 0076216, validated for the first time in a set of 19 physiological human tissues, positively correlated with that of their host gene (Rho value = 0.579 and 0.681, p-value = 0.026 and 0.013, respectively). Our data suggest that PIM1 is an oncogene involved in the recurrence of WHO grade 2 MNG and that the upstream ceRNA network, comprising circRNAs 0076215 and 0076216 and miRNAs 16-5p and 195-5p, is responsible for its upregulation through a feed-forward loop.

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Giuseppe Sotera www.mdpi.com