Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of the epidermal growth factor receptor (EGFR) signaling pathway. The aim of this study was to investigate the underlying mechanism of LRIG1 in the regulation of vasculogenic mimicry (VM) formation in glioma cells. We constructed an enhanced green fluorescent protein plasmid (pEGFP) system, pEGFP-C1-LRIG1, for overexpression of LRIG1, and transfected it into human glioma cell line SHG-44. Under hypoxic conditions induced by CoCl 2 , we investigated the effects of LRIG1 overexpression on VM formation and VM-dependent malignant behaviors including migration, invasion, and proliferation. Additionally, we explored the effects of LRIG1 on the expression levels of major components of the EGFR/PI3K/AKT pathway as well as E-cadherin and vimentin. We found that LRIG1 overexpression is able to inhibit hypoxia-induced VM formation, migration, invasion, and proliferation. Furthermore, LRIG1 overexpression counteracts hypoxiainduced increase in the expression of phosphorylated EGFR (pEGFR), PI3K (pPI3K), and AKT (pAKT) and reverts hypoxia-induced alteration in E-cadherin and vimentin expression levels. In LRIG1 knockdown SHG-44 cells, however, hypoxia-induced VM formation and alteration in E-cadherin and vimentin expression levels were exacerbated. These results suggest that the inhibitory effects of LRIG1 are most likely mediated by suppression of the EGFR/PI3K/AKT pathway and epithelial-mesenchymal transition (EMT) process. Our findings provide compelling evidence implicating LRIG1 in glioma pathophysiology, suggesting that gene therapy using LRIG1 may serve as a treatment for this disease.

MicroRNA-361-5p (miR-361-5p) has been reported to be dysregulated in various human cancer types. However, the function of miR-361-5p in glioma remains unknown. In the present study, we aimed to investigate the biological functions of miR-361-5p in regulating glioma progression and the underlying molecular mechanism. We found that miR-361-5p was significantly decreased in glioma tissues and cell lines as detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Functional analysis revealed that miR-361-5p overexpression significantly inhibited glioma cell migration, invasion and epithelial-mesenchymal transition (EMT) whereas suppression of miR-361-5p showed opposite effects. Bioinformatic analysis showed that Twist1, a critical EMT inducer, was a predicted target of miR-361-5p which was validated by dual-luciferase reporter assay, RT-qPCR and western blot analysis. Further analysis indicated that miR-361-5p regulates the Twist1/Bmi-1 signaling axis. Rescue experiments showed that restoration of Twist1 expression significantly reversed the suppressive effect of miR-361-5p on cell migration, invasion and EMT. Taken together, the present study demonstrated an important role of miR-361-5p in glioma - which regulated the EMT of glioma cells by targeting and regulating Twist1. These findings provide novel insight into understanding the role and mechanism of miR-361-5p in regulating the biolo-gical behavior of glioma cells and suggest that miR-361-5p is a novel potential therapeutic target for glioma.

MicroRNA-194 (miR-194) is frequently dysregulated in many types of cancer. However, the function of miR-194 in glioma remains unknown. In the present study, we aimed to investigate the biological functions of miR-194 in glioma and the potential molecular mechanism of miR-194 involved in glioma progression. We found that miR-194 expression was significantly reduced in glioma specimens and cell lines, as detected by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. The overexpression of miR-194 inhibited while the suppression of miR-194 promoted cell migration, invasion and epithelial mesenchymal transition (EMT) in glioma cells. Bioinformatics analysis showed that the B cell-specific moloney murine leukemia virus insertion site 1 (Bmi1) was a direct target of miR-194, which was validated by dual-luciferase reporter assay, RT-qPCR and western blot analysis. The restoration of Bmi1 expression significantly abrogated the suppressive effect of miR-194 on glioma cell EMT. Taken together, the present study suggests that miR-194 inhibits glioma cell EMT by targeting Bmi1 providing novel insights into understanding the pathogenesis of glioma. The restoration of miR-194 may be a potential therapeutic strategy for glioma treatment.

Bone marrow-derived mesenchymal stem cells (BMSCs) are promising gene vehicles for cancer gene therapy. In our previous study, we reported that BMSCs expressing interleukin (IL)-18 effectively inhibit the growth of glioma in rats. In the present study, we further detected the effect of BMSCs co-expressing IL-18 and interferon (IFN)-β, both of which are immunostimulatory cytokines. BMSCs were genetically engineered to express IL-18 and IFN-β by transfection of recombinant lentivirus-mediated gene transfer. Results showed that BMSCs co-expressing the two cytokines displayed more significant inhibition effect on glioma cell growth in vitro when compared with BMSCs solely expressing IL-18 or IFN-β. Treatment of BMSCs co-expressing IL-18 and IFN-β significantly prolonged the survival and inhibited tumor growth in a rat intracranial glioma model. Furthermore, these genetically engineered BMSCs remarkably promoted cell apoptosis, antitumor cytokine production and CD4+ and CD8+ T-cell infiltration in intracranial glioma tissues than BMSCs solely expressing IL-18 or IFN-β. Results of the present study suggested that IL-18 and IFN-β had a synergistic effect on glioma inhibition. Moreover, results provided evidence that delivery of IL-18 and IFN-β by BMSCs may be an excellent and promising approach to develop an effective treatment protocol for glioma therapy.

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