The Effect Of MiR-199a On Tumor Proliferation, Migration And Invasion In Glioma And Its Molecular Mechanism

Glioma turns to be the most common tumor in the central nervous system,including astrocytomas(originated from astrocytes),ependymal cell tumors(originated from ependymal cells)and oligodendroglioma(originated from Oligodendrocyte)etc.Glioma is one of the leading cancer-related causes of death in the world.Low grade gliomasaccounted for only about 15%-25%in all glioma cases.The five year survival rate of high grade glioma is less than 5%,they were low differentiated and highly aggressive.The clinical treatments of glioma were surgery and radio-chemotherapy with adjuvant therapy.The insidious onset of the initial stage gliomaare not characterized by typical symptoms,result in the later diagnosis of the disease.Moreover,as a highly invasive tumor type,glioma’s lesions often have no clear boundaries with the adjacent normal brain tissues and result in the poor effect of surgical treatment in high grade glioma.On the other hand,high grade glioma is insensitive to radio-chemotherapy.All these features of glioma result in the poor prognosis in clinical treatment.MicroRNAs(miRNAs)are small endogenous non-coding RNAs,with a length of 20-25 nucleotides.MiRNAs are widely distributed in animal and plant cells and are highly conserved in biological evolution.MiRNAs play an important role in the regulation of the biological functions of the cells through the post transcriptional regulation.The abnormal expression of miRNAs is common in all type of tumors,and is closely related to the occurrence and development of cancers.In order to study the effect of miR-199a on glioma progression,we collected 9 normal brain tissues and 24 glioma tissues.In this study,we found that miR-199a expression levels were downregulated in human glioma specimens compared to adjacent normal tissues.MiR-199a expression levels were strongly correlated with clinical stages.Furthermore,kinase suppressor of RAS 1(K-RAS),an oncogene,was a direct target of miR-199a,and K-RAS expression levels were inversely correlated with miR-199a expression levels in human glioma specimens.Overexpression of miR-199a suppressed AKT and ERK activation,decreased HIF-1α and VEGF expression,inhibited cell proliferation and migration,whereas forced expression of K-RAS restored the inhibitory effect of miR-199a on cell proliferation and migration.Moreover,miR-199a renders glioma cells more sensitive to temozolomide(TMZ)treatment by targeting K-RAS.In vivo experiment validated that miR-199a functioned as a tumor suppressor to inhibit tumor growth by targeting K-RAS and suppressed AKT,ERK activation and HIF-1α expression.Taken together,these results revealed that downregulated miR-199a levels in human glioma tissues result in increased K-RAS expression,which is associated with glioma occurrence and advanced stages.MiR-199a may be a potential biomarker evaluated for staging and treatment response of glioma.