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

Davide Barbagallo, Angela Caponnetto, Duilia Brex, Federica Mirabella, Cristina Barbagallo, Giovanni Lauretta, Antonio Morrone, Francesco Certo, Giuseppe Broggi, Rosario Caltabiano, Giuseppe M. Barbagallo, Vittoria Spina-Purrello, Marco Ragusa, Cinzia Di Pietro, Thomas B. Hansen, Michele Purrello

Research output: Contribution to journalArticle

Abstract

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
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    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. (2019). CircSMARCA5 regulates VEGFA mRNA splicing and angiogenesis in glioblastoma multiforme through the binding of SRSF1. Cancers, 11(2), [194]. https://doi.org/10.3390/cancers11020194