RAS Oncogene in Brain Tumors, Let-7 MicroRNA Involvement

RAS oncogenes are master regulators of cancers. Somatic mutation in KRAS, HRAS and NRAS genes account for approximately 30% of human cancers. KRAS is the most frequently mutated isoform in RAS-driven cancers. Brain cancers are RAS-driven cancers despite have no RAS mutation or amplification and its pivotal role in brain tumorigenesis has been well documented. Indeed, it’s generally accepted that glioblastoma shows aberrant activation of RAS/MAPK cascade due to mutations in upstream and downstream regulators. Since pioneering study reporting that let-7 miRNA acted as tumor suppressor by repressing RAS oncogene, growing evidence has suggested the importance of miRNA targeting the RAS-MAPK in brain oncogenesis. Let-7 family members are direct and strong regulator of the RAS family. KRAS, NRAS and HRAS mRNAs contain let-7 binding sites in 3’UTR sequences with clinical outcomes in some cancer. Although the expression levels of let-7 miRNA family are not reduced in brain tumors (with few exceptions), growing evidences show that let-7 miRNA inhibits the malignant behavior proliferation, migration and invasion of glioma cells and glioma stem-like cells as well as the tumor size in nude mice xenograft transplanted glioblastoma (GBM) via KRAS inhibition. More recently, genetic loss of let-7 is involved in neuroblastoma oncogenesis placing let-7 disruption at the center of neuroblastoma pathogenesis. In addition, loss of let-7 increases resistance to certain chemotherapeutic drugs and to radiation therapy in GBM. We aim this review at summarizing and updating current knowledge on the contribution of let-7 miRNA interplay with KRAS to oncogenesis of brain tumors.