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

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.

DGCR8/ZFAT-AS1 Promotes CDX2 Transcription in a PRC2 Complex-Dependent Manner to Facilitate the Malignant Biological Behavior of Glioma Cells

“…[31][32][33] RBP SRSF1 bound to circSMARCA5 regulates VEGFA mRNA splicing and angiogenesis in glioblastoma multiforme. 20 It has also been found that circSMARCA5 may inhibit the migration of glioblastoma multiforme cells by tethering the RBP SRSF1. 21 In the present study, DGCR8 protein levels were markedly elevated in glioma tissues and in U87 and U251 cells.…”

“…19 It has been reported that RBP SRSF1 regulates cell migration, VEGFA mRNA splicing, and angiogenesis in glioblastoma multiforme by binding to circSMARCA5. 20,21 However, the regulatory role and potential mechanisms of DGCR8 and ZFAT-AS1 affecting the biological behavior of glioma have not yet been elucidated.…”

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

“…This observation correlated with the reduced migration capacity/propensity of GBM cells over-expressing circSMARCA5. Interestingly, circSMARCA5 acts as a sponge for the oncogenic splicing factor SRSF1, thus limiting its activity [119,120]. SRSF1 is up-regulated in GBM patients and promotes pro-angiogenic VEGF isoforms [120,121].…”

“…Interestingly, circSMARCA5 acts as a sponge for the oncogenic splicing factor SRSF1, thus limiting its activity [119,120]. SRSF1 is up-regulated in GBM patients and promotes pro-angiogenic VEGF isoforms [120,121]. Thus, down-regulation of circSMARCA5 in GBM unleashes a trans-acting splicing regulator to promote pro-angiogenic features.…”

Tumor-Suppressive Function of lncRNA-MEG3 in Glioma Cells by Regulating miR-6088/SMARCB1 Axis

“…Glioma, a malignant tumor, is the most common intracranial primary cancer with the highest morbidity and mortality rates worldwide [1][2][3][4]. In spite of the great efforts on the clinical development, the long-term prognosis and postoperative outcomes for patients are still far from being satisfactory [5,6].…”