Barbagallo Davide, Caponnetto Angela, Brex Duilia, Mirabella Federica, Barbagallo Cristina, Lauretta Giovanni, Morrone Antonio, Certo Francesco, Broggi Giuseppe, Caltabiano Rosario, Barbagallo Giuseppe M, Spina-Purrello Vittoria, Ragusa Marco, Di Pietro Cinzia, Hansen Thomas B, Purrello Michele
Department of Biomedical and Biotechnological Sciences-Section of Biology and Genetics "Giovanni Sichel", University of Catania, 95123 Catania, Italy.
Multidisciplinary Research Center on Brain Tumors Diagnosis and Therapy, University of Catania, 95123 Catania, Italy.
Cancers (Basel). 2019 Feb 7;11(2):194. doi: 10.3390/cancers11020194.
Circular RNAs are a large group of RNAs whose cellular functions are still being investigated. We recently proposed that circSMARCA5 acts as sponge for the splicing factor Serine and Arginine Rich Splicing Factor 1 (SRSF1) in glioblastoma multiforme (GBM). After demonstrating by RNA immunoprecipitation a physical interaction between SRFS1 and circSMARCA5, we assayed by real-time PCR in a cohort of 31 GBM biopsies and 20 unaffected brain parenchyma controls (UC) the expression of total, pro-angiogenic (Iso8a) and anti-angiogenic (Iso8b) mRNA isoforms of Vascular Endothelial Growth Factor A (VEGFA), a known splicing target of SRSF1. The Iso8a to Iso8b ratio: (i) increased in GBM biopsies with respect to UC (-value < 0.00001); (ii) negatively correlated with the expression of circSMARCA5 (-value = -0.46, -value = 0.006); (iii) decreased in U87-MG overexpressing circSMARCA5 with respect to negative control (-value = 0.0055). Blood vascular microvessel density, estimated within the same biopsies, negatively correlated with the expression of circSMARCA5 (-value = -0.59, -value = 0.00001), while positively correlated with that of SRSF1 (-value = 0.38, -value = 0.00663) and the Iso8a to Iso8b ratio (-value = 0.41, -value = 0.0259). Kaplan-Meier survival analysis showed that GBM patients with low circSMARCA5 expression had lower overall and progression free survival rates than those with higher circSMARCA5 expression (-values = 0.033, 0.012, respectively). Our data convincingly suggest that circSMARCA5 is an upstream regulator of pro- to anti-angiogenic VEGFA isoforms ratio within GBM cells and a highly promising GBM prognostic and prospective anti-angiogenic molecule.
环状RNA是一大类RNA，其细胞功能仍在研究中。我们最近提出，环状SMARCA5在多形性胶质母细胞瘤（GBM）中作为剪接因子丝氨酸和精氨酸丰富剪接因子1（SRSF1）的海绵。通过RNA免疫沉淀证明SRFS1与环状SMARCA5之间存在物理相互作用后，我们通过实时PCR在31例GBM活检样本和20例未受影响的脑实质对照（UC）中检测了血管内皮生长因子A（VEGFA）的总mRNA亚型、促血管生成（Iso8a）和抗血管生成（Iso8b）mRNA亚型的表达，VEGFA是SRSF1的已知剪接靶点。Iso8a与Iso8b的比值：（i）在GBM活检样本中相对于UC升高（P值<0.00001）；（ii）与环状SMARCA5的表达呈负相关（r值=-0.46，P值=0.006）；（iii）在过表达环状SMARCA5的U87-MG细胞中相对于阴性对照降低（P值=0.0055）。在相同活检样本中估计的血管微血管密度与环状SMARCA5的表达呈负相关（r值=-0.59，P值=0.00001），而与SRSF1的表达呈正相关（r值=0.38，P值=0.00663）以及与Iso8a与Iso8b的比值呈正相关（r值=0.41，P值=0.0259）。Kaplan-Meier生存分析表明，环状SMARCA5表达低的GBM患者的总生存率和无进展生存率低于环状SMARCA5表达高的患者（P值分别为0.033、0.012）。我们的数据令人信服地表明，环状SMARCA5是GBM细胞内促血管生成与抗血管生成VEGFA亚型比值的上游调节因子，是一种极有前景的GBM预后和前瞻性抗血管生成分子。
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