Role And Molecular Mechanism Of MiR-128in Glioma

Glioma is the most common and most aggressive type of primary brain tumors,which accounts for~40%of all central nervous system tumors. Glioma may occur inany part of the central nervous system and at any age. At this stage, the cardinaltherapeutic method is surgery. Glioma has the characteristics of highly invasion rateand rich angiogenesis, so it is impossible to completely remove all lesions withsurgery. Despite the surgical diagnosis, technique and adjuvant treatment havedeveloped rapidly, the recurrence rate of postoperative is high yet and five-yearsurvival rate has not increased significantly. The study of the pathogenesismechanism further is quite important to seek new methods of diagnosis and treatmentof glioma.MicroRNAs (miRNAs) are a class of endogenous, evolutionarily conserved,short sequence，non-coding RNAs discovered recently and regulate gene expressionsposttranscriptionally. MiRNAs regulate physiological and pathological process, suchas cell growth, cell cycle and apoptosis. The expressions of miRNAs alter in tumorsand they may function as oncogenes or tumor suppressors, which related with tumorgrowth closely.We analyzed the expression of miR-128in eight normal brain tissues and each ofthirteen glioma tissues at Grades Ⅱ/Ⅲ/Ⅳ, and found that the expressions of miR-128in glioma tissues were decreased when compared to the normal brain tissues. Theresult is consistent with other researchers’, suggesting that miR-128plays animportant role in glioma. We found p70S6K1is the directly target of miR-128through bioinformatics software and reporter gene analysis. p70S6K1is an keydownstream protein of mTOR, which regulates cell growth, proliferation, cycle andapoptosis. The activation of p70S6K1is associated with hypoxia-inducible factor1(HIF-1α) and Vascular endothelial factor (VEGF) which are important factors intumor angiogenesis. We constructed stable cell lines expressing miR-128and study the role of miR-128on molecular lever and animal level in glioma. We found thatover-expression of miR-128inhibits glioma proliferation in vitro and vivo viadecreasing protein expression of p70S6K1. The expressions of HIF-1α and VEGF arealso down-regulated. In addition, we established tumor angiogenesis model usingnude mice to detecte hemoglobin levels and found miR-128inhibited angiogenesis inglioma as well.In short, miR-128inhibits tumor growth and angiogenesis by targeting p70S6K1and regulating its downstream signalings. In this study，we found a new target ofmiR-128and clarified its molecular mechanisms of tumor growth inhibition in glioma.These results provide a theoretical basis for gliomas diagnosis, treatment andprognosis of miRNAs application in the future.