Sotera Giuseppe, Forte Carla, D'Urso Daniele Giuseppe, Reina Domenica, Zuccaro Noemi, Toscano Andrea Giuseppe, Caponnetto Angela, Barbagallo Cristina, Broggi Giuseppe, Certo Francesco, Ragusa Marco, Caltabiano Rosario, Di Pietro Cinzia, Barbagallo Giuseppe Maria Vincenzo, Purrello Michele, Barbagallo Davide
Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Neurological Surgery, Policlinico Rodolico-San Marco University Hospital, University of Catania, Via Santa Sofia, 87, 95123 Catania, Italy.
Department of Biological, Geological and Environmental Sciences, University of Catania, Corso Italia, 57, 95129 Catania, Italy.
Int J Mol Sci. 2025 Aug 26;26(17):8263. doi: 10.3390/ijms26178263.
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, -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.
在散发性脑膜瘤（MNG）肿瘤中，一种基于34种转录本表达的生物标志物（34HR-MNG）最近被描述为能够预测其预后，包括复发情况。为了更好地研究调节34HR-MNG转录本表达的分子机制，并预测它们在MNG复发中的功能作用，我们通过计算机模拟方法构建了一个竞争性内源性RNA（ceRNA）网络。分别通过MiRTarbase和ENC ORI数据库检索靶向34HR-MNG转录本的miRNA和相应的海绵状环状RNA（circRNA）。通过查询RNA测序数据集GSE189672，属于34HR-MNG转录本的候选circRNA宿主基因的表达分别与89例世界卫生组织（WHO）1级和20例WHO 2级MNG的特定分子和临床特征相关。通过qRT-PCR验证了候选circRNA及其宿主基因的表达。在34HR-MNG转录本中，原癌基因丝氨酸/苏氨酸激酶Pim-1（PIM1）在（i）WHO 2级与1级以及（ii）复发的与未复发的WHO 2级MNG中显著上调。在复发的WHO 2级MNG中，PIM1表达分别与Ki-67和NF2的表达呈正相关和负相关。均由PIM1宿主基因产生的circRNA 0076215和0076216被预测可海绵化miRNA 16-5p和195-5p，这两种是MNG中的肿瘤抑制因子，反过来靶向PIM1。circRNA 0076215和0076216的表达首次在一组19种生理人体组织中得到验证，与它们的宿主基因表达呈正相关（Rho值分别为0.579和0.681，P值分别为0.026和0.013）。我们的数据表明，PIM1是一种参与WHO 2级MNG复发的癌基因，并且上游ceRNA网络，包括circRNA 0076215和0076216以及miRNA 16-5p和195-5p，通过前馈环负责其上调。
