MicroRNA-566 modulates vascular endothelial growth factor by targeting Von Hippel-Landau in human glioblastoma in vitro and in vivo

Abstract

MicroRNAs (miRNAs) are able to function as either oncogenes or tumor suppressor genes in tumorigenesis, and have been proposed as novel targets for anticancer treatment. It has previously been suggested that miRNAs have important roles in the initiation and progression of glioblastoma; however, the effects of miR‑566 in glioblastoma are currently unclear. The present study aimed to demonstrate that miR-566 can modulate vascular endothelial growth factor (VEGF) by targeting Von Hippel‑Lindau (VHL) in glioblastoma in vitro and in vivo by inhibiting the expression of miR-566. Glioblastoma is a highly vascularized tumor, which exhibits increased expression of angiogenic factors, including VEGF, which are crucial in the process of glioblastoma angiogenesis. Existing research has demonstrated that VHL is a tumor suppressor gene that is associated with various tumors. In addition, VHL is able to regulate the expression of VEGF by promoting the degradation of hypoxia‑inducible factor‑1α via ubiquitination. It has been predicted, using bioinformatics, that the VHL gene is regulated by miR‑566. Therefore, the present study hypothesized that miR‑566 may regulate VEGF expression by targeting VHL during the angiogenic process of glioblastoma multiforme. The results of the present study demonstrated that inhibition of miR‑566 expression increases the expression levels of VHL, decreases the expression levels of VEGF, and inhibits the invasive and migratory abilities of glioblastoma. In addition, VHL was identified as a functional target of miR‑566.

Lentivirus-mediated knockdown of chondroitin polymerizing factor inhibits glioma cell growth in vitro

“…Glioma, particularly glioblastoma, has a poor prognosis (4,13). It is one of the most common highly vascularized malignant tumors of the CNS, with a ≤12-month median survival period (5,14).…”

“…In adults, glioma is the most common type of malignant tumor of the brain and central nervous system, characterized by rapid progression, aggressive behavior, frequent recurrence and poor prognosis (1,2). Despite advances in diagnosis and treatment, frequent recurrence and a low cure rate of glioma remain due to the rapid proliferation and high invasiveness of this disease, particularly for glioblastoma multiforme patients (3,4). It is in essence a genetic disease with overexpression of oncogenes and deletions or mutations of tumor-suppressor genes, which lead to the uncontrolled proliferation of cancer cells (5,6).…”

Hypoxia, Inflammation and Necrosis as Determinants of Glioblastoma Cancer Stem Cells Progression

“…In fact, in this GSC line, we observed a modulation of VEGF mRNA by hypoxia that was not paralleled by a modulation of VEGF protein expression (compare Figure 1C with Figure 2C). Even if we did not investigate into that, we think that such a discrepancy might be due to: (i) a post-transcriptional control by miRNA that prevent expression of VEGF from mRNA either directly as in the case of miR-16 [49] or indirectly by targeting VHL protein as in the case of miR-566 [50]; (ii) the intratumoral heterogeneity of line #83 that contains tumor cells with different metabolic behavior that when sub-cloned gave rise to cell lines belonging to separate metabolic clusters [51]. In the latter case, this heterogeneity might reflect in opposite trends of VEGF protein expression showing, on average, no significant increase.…”

MicroRNA‑21‑5p induces the metastatic phenotype of human cervical carcinoma cells in vitro by targeting the von Hippel‑Lindau tumor suppressor

“…A prior study suggested that tuberous sclerosis complex protein 1 expression is affected by VHL gene alterations and HIF-1α expression in renal cell carcinoma (23). It was also demonstrated that miR-566 regulates vascular endothelial growth factor (VEGF) by targeting VHL in human glioblastoma in vitro and in vivo (24). Another study suggested that hsa-miR-331-3p downregulates VHL expression in hepatocellular carcinoma cell lines by targeting its 3'-UTR (25), and that miR-101 targets VHL to promote HIF-1α-mediated apoptosis and cell cycle arrest (26).…”