CD73 Molecule Inhibitor Upregulates miR16 Expression in Experimental Glioblastoma and Inhibits Angiogenesis by Targeting VEGF

Abstract

The function of CD73 (Cluster of Differentiation 73), an enzyme involved in the formation of adenosine (ADO), in the development of glioblastomas has been demonstrated. Indeed, ADO helps tumor angiogenesis by stimulating endothelial cell migration, proliferation, and tube formation. However, the details of the molecular mechanisms are not yet fully understood. Given the importance of angiogenesis in cancer progression, invasion, and metastasis, this study aimed to investigate how the inhibition of CD73 by adenosine-5′-(α, β-methylene) diphosphate (APCP) affects the angiogenesis process of experimental orthotopic glioblastoma at mRNAs, microRNAs, and protein levels. According to the real-time-polymerase chain reaction (RT-PCR) results, inhibition of CD73 decreased the angiogenesis of glioblastoma by reducing the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1α) by ****P < 0.0001 and **P < 0.01, respectively. Furthermore, immunohistochemical staining showed that this treatment protocol attenuated the expression of VEGF and CD31. Moreover, APCP treatment significantly increased miR-16 expression in glioblastoma model rats by P < 0.001, but no significant change in miR-29A expression was observed. The results showed that the treatment did not lead to systemic damage or significant weight loss. Our results suggest that inhibition of CD73 may reduce the formation of new tumor vessels by inhibiting the VEGF, HIF-1α, and CD31 in this process. Therefore, CD73 may be a practical target and provide new opportunities to improve the treatment of malignant brain tumors.