Role And Mechanism Of MiR-124in Regulating Tumor Growth And Angiogenesis Of Glioma

Glioma represents one of the most aggressive and lethal human brain tumors, which starts in the brain or spine and arises from glial cells. Glioma makes up about40%of all brain and central nervous system tumors. In recent years, the cardinal therapeutic method is surgery, combining with chemotherapy and/or radiotherapy. Since glioma has the characteristics of highly invasion rate and rich angiogenesis, it is impossible to completely remove all lesions with surgery, the recurrence rate of postoperative is high yet and five-year survival rate has not increased significantly. Therefore, to further explore the pathogenesis of glioma, looking for new methods of diagnosis and treatment is very important.MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs composed of about18-24nucleotides with highly conserved in evolution. By regulating gene expression through targeting3’-untranslated region (3’-UTR) of mRNAs, miRNAs regulate cell differentiation, apoptosis, cell cycle, and generation. Characteristic changes of expression type and quantity in a variety of tumors, miRNAs act as oncogenes or tumor suppressors in the genesis and development of tumor and miRNA-based therapies are obtained more and more attentions.We analyzed the expression of miR-124in six normal brain tissues and each of eight glioma tissues at Grades Ⅱ/Ⅲ/Ⅳ, and found that the expression of miR-124in glioma tissues was decreased when compared to the normal brain tissues. The result was consistent with other researchers, and strongly correlated with clinical WHO grades of glioma, suggesting that miR-124played an important role in glioma. We constructed stable cell lines expressing miR-124and study the role of miR-124on molecular level and animal level in glioma. We found that in glioma cells, the overexpression of miR-124could significantly inhibit cell growth rate and invasive ability, and could suppress angiogenesis, tumor growth in nude mice in vivo. In order to further study the molecular mechanism of its potential, predicted by bioinformatics software and report gene detection, we found that miR-124could be directly targeted R-RAS and N-RAS. R-RAS and N-RAS were involved in cell signal transduction, their activation could affect the downstream PI3K/AKT and RAF/ERK1/2, the two most important signaling pathways on tumor growth and angiogenesis. We found that miR-124could inhibit tumor growth and angiogenesis through the downstream signaling pathways by targeting R-RAS and N-RAS. The expressions of HIF-la and VEGF were also down-regulated. We also found that, in clinical glioma specimens, compared with normal brain tissue, protein levels of R-RAS and N-RAS were up-regulated, and inversely correlated with miR-124expression levels.Taken together, these results revealed that miR-124levels in human tumor tissues were associated with glioma occurrence and angiogenesis. In this study, we found that miR-124inhibited glioma progression both in vitro and in vivo, revealed that miR-124and its new targets R-RAS/N-RAS were associated with glioma development, illustrated the molecular mechanisms of miR-124inhibit the glioma growth by targeting R-RAS and N-RAS. Thus, miR-124might be used as a new diagnostic marker and therapeutic target for glioma, and could be helpful in developing microRNA-based drugs for treating glioma in the future.