Hergalant Sébastien, Casse Jean-Matthieu, Oussalah Abderrahim, Houlgatte Rémi, Helle Déborah, Rech Fabien, Vallar Laurent, Guéant Jean-Louis, Vignaud Jean-Michel, Battaglia-Hsu Shyue-Fang, Gauchotte Guillaume
INSERM, U1256, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France.
Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy (CHRU), Vandoeuvre-lès-Nancy, France.
Front Oncol. 2023 Aug 2;13:1158773. doi: 10.3389/fonc.2023.1158773. eCollection 2023.
Meningiomas are the most common type of primary central nervous system tumors. In about 80% cases, these tumors are benign and grow very slowly, but the remainder 20% can unlock higher proliferation rates and become malignant. In this study we examined two miRs, miR-16 and miR-519, and evaluated their role in tumorigenesis and cell growth in human meningioma.
A cohort of 60 intracranial grade 1 and grade 2 human meningioma plus 20 healthy meningeal tissues was used to quantify miR-16 and miR-519 expressions. Cell growth and dose-response assays were performed in two human meningioma cell lines, Ben-Men-1 (benign) and IOMM-Lee (aggressive). Transcriptomes of IOMM-lee cells were measured after both miR-mimics transfection, followed by integrative bioinformatics to expand on available data.
In tumoral tissues, we detected decreased levels of miR-16 and miR-519 when compared with arachnoid cells of healthy patients (miR-16: P=8.7e-04; miR-519: P=3.5e-07). When individually overexpressing these miRs in Ben-Men-1 and IOMM-Lee, we observed that each showed reduced growth (P<0.001). In IOMM-Lee cell transcriptomes, downregulated genes, among which ELAVL1/HuR (miR-16: P=6.1e-06; miR-519:P=9.38e-03), were linked to biological processes such as mitotic cell cycle regulation, pre-replicative complex, and brain development (FDR<1e-05). Additionally, we uncovered a specific transcriptomic signature of miR-16/miR-519-dysregulated genes which was highly enriched in HuR targets (>6-fold; 79.6% of target genes).
These results were confirmed on several public transcriptomic and microRNA datasets of human meningiomas, hinting that the putative tumor suppressor effect of these miRs is mediated, at least in part, via HuR direct or indirect inhibition.
脑膜瘤是原发性中枢神经系统肿瘤中最常见的类型。在大约80%的病例中，这些肿瘤是良性的，生长非常缓慢，但其余20%可能具有更高的增殖率并变为恶性。在本研究中，我们检测了两种microRNA（miR-16和miR-519），并评估了它们在人类脑膜瘤肿瘤发生和细胞生长中的作用。
使用一组60例颅内1级和2级人类脑膜瘤以及20例健康脑膜组织来量化miR-16和miR-519的表达。在两种人类脑膜瘤细胞系Ben-Men-1（良性）和IOMM-Lee（侵袭性）中进行细胞生长和剂量反应测定。在转染miR模拟物后测量IOMM-lee细胞的转录组，随后进行综合生物信息学以扩展现有数据。
在肿瘤组织中，与健康患者的蛛网膜细胞相比，我们检测到miR-16和miR-519水平降低（miR-16：P = 8.7e-04；miR-519：P = 3.5e-07）。当在Ben-Men-1和IOMM-Lee中单独过表达这些microRNA时，我们观察到每个都显示出生长减少（P < 0.001）。在IOMM-Lee细胞转录组中，下调的基因，其中ELAVL1/HuR（miR-16：P = 6.1e-06；miR-519：P = 9.38e-03），与有丝分裂细胞周期调控、复制前复合体和脑发育等生物学过程相关（错误发现率<1e-05）。此外，我们发现了miR-16/miR-519失调基因的特定转录组特征，其在HuR靶标中高度富集（>6倍；79.6%的靶标基因）。
这些结果在人类脑膜瘤的几个公共转录组和microRNA数据集中得到证实，表明这些microRNA的假定肿瘤抑制作用至少部分是通过HuR的直接或间接抑制介导的。
