circSMARCA5-SRSF1 interaction is functionally involved in GBM pathogenesis

Abstract

Glioblastoma multiforme (GBM) is the most aggressive human brain tumor with a median survival of 15 months. The standard treatments of GBM and the total medical resection are unable to contrast this mortal cancer. For these reason new diagnostic approaches and therapies are needed. The identification of molecular features of this cancer may allow to create a personalized therapy. Circular RNAs (circRNAs) are a new class of non-coding RNAs (ncRNAs) highly enriched in brain, stable within the cells, detectable in body fluids and having a potential role and biological importance still object of debate. This thesis investigated the putative involvement of circRNAs in GBM pathogenesis. It has been demonstrated that circSMARCA5 is downregulated in GBM biopsies, its expression is associated to the glioma grade malignancy and it negatively regulates migration of U87MG cells. Moreover, it has been proved the physical interaction between circSMARCA5 and one of its predicted interactor Serine/arginine-rich splicing factor 1 (SRSF1). Interesting splicing targets of SRSF1 are the serine and arginine rich splicing factor 3 (SRSF3) and the vascular endothelial growth factor A (VEGFA). It has been proposed that circSMARCA5 may regulate the alternative splicing of SRSF3 in favor of the formation of a stable oncoprotein in GBM. It also regulates the alternative splicing of VEGFA mRNA through the binding to SRSF1. In addition, blood vascular microvessel density evaluated in GBM negatively correlates with the expression of circSMARCA5, while positively correlates with that of SRSF1 and pro-to-anti-angiogenic VEGFA isoform ratio. GBM patients with low circSMARCA5 expression have lower overall and progression free survival rates. Based on these findings, CircSMARCA5 could be considered a promising druggable tumor suppressor in GBM. Moreover, its interaction with SRSF1 makes circSMARCA5 an upstream regulator of pro- to anti-angiogenic VEGFA isoforms ratio within GBM cells and a highly promising GBM prospective anti-angiogenic molecule.