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CircSMARCA5 regulates VEGFA mRNA splicing and angiogenesis in glioblastoma multiforme through the binding of SRSF1

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DOI

  • Davide Barbagallo, Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics “Giovanni Sichel”, Università di Catania, Multidisciplinary Research Center on Brain Tumors Diagnosis and Therapy
  • ,
  • Angela Caponnetto, Università di Catania
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  • Duilia Brex, Università di Catania
  • ,
  • Federica Mirabella, Università di Catania
  • ,
  • Cristina Barbagallo, Università di Catania
  • ,
  • Giovanni Lauretta, Università di Catania
  • ,
  • Antonio Morrone, Università di Catania
  • ,
  • Francesco Certo, Università di Catania
  • ,
  • Giuseppe Broggi, Università di Catania
  • ,
  • Rosario Caltabiano, Università di Catania
  • ,
  • Giuseppe M. Barbagallo, Università di Catania
  • ,
  • Vittoria Spina-Purrello, Università di Catania
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  • Marco Ragusa, Università di Catania, Oasi Research Institute-IRCCS
  • ,
  • Cinzia Di Pietro, Università di Catania
  • ,
  • Thomas B. Hansen
  • Michele Purrello, Università di Catania

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.

Original languageEnglish
Article number194
JournalCancers
Volume11
Issue2
Number of pages12
ISSN2072-6694
DOIs
Publication statusPublished - 1 Feb 2019

    Research areas

  • Alternative splicing, Angiogenesis, Circular RNA, Glioblastoma multiforme, Hsa_circ_0001445, RNA binding proteins, VEGFA

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