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Open AccessArticle

CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1

1
Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics “Giovanni Sichel”, University of Catania, 95123 Catania, Italy
2
Multidisciplinary Research Center on Brain Tumors Diagnosis and Therapy, University of Catania, 95123 Catania, Italy
3
Department of Medical, Surgical and Advanced Technological Sciences “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
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Department of Biomedical and Biotechnological Sciences—Section of Medical Biochemistry, University of Catania, 95123 Catania, Italy
5
Oasi Research Institute-IRCCS, 94018 Troina, Italy
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Department of Molecular Biology and Genetics (MBG), Aarhus University, 8000 Aarhus C, Denmark
7
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus C, Denmark
*
Authors to whom correspondence should be addressed.
Senior authors.
Cancers 2019, 11(2), 194; https://doi.org/10.3390/cancers11020194
Received: 30 December 2018 / Revised: 24 January 2019 / Accepted: 6 February 2019 / Published: 7 February 2019
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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 (p-value < 0.00001); (ii) negatively correlated with the expression of circSMARCA5 (r-value = −0.46, p-value = 0.006); (iii) decreased in U87-MG overexpressing circSMARCA5 with respect to negative control (p-value = 0.0055). Blood vascular microvessel density, estimated within the same biopsies, negatively correlated with the expression of circSMARCA5 (r-value = −0.59, p-value = 0.00001), while positively correlated with that of SRSF1 (r-value = 0.38, p-value = 0.00663) and the Iso8a to Iso8b ratio (r-value = 0.41, p-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 (p-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. View Full-Text
Keywords: circular RNA; hsa_circ_0001445; RNA binding proteins; alternative splicing; glioblastoma multiforme; angiogenesis; VEGFA circular RNA; hsa_circ_0001445; RNA binding proteins; alternative splicing; glioblastoma multiforme; angiogenesis; VEGFA
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Barbagallo, D.; Caponnetto, A.; Brex, D.; Mirabella, F.; Barbagallo, C.; Lauretta, G.; Morrone, A.; Certo, F.; Broggi, G.; Caltabiano, R.; Barbagallo, G.M.; Spina-Purrello, V.; Ragusa, M.; Di Pietro, C.; Hansen, T.B.; Purrello, M. CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1. Cancers 2019, 11, 194.

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