Abstract
The highly conserved RAS-mitogen activated protein kinase (MAPK) signaling pathway is involved in a wide range of cellular processes including differentiation, proliferation, and survival. Somatic mutations in genes encoding RAS-MAPK components frequently occur in many tumors, making the RAS-MAPK a critical pathway in human cancer. Since the pioneering study reporting that let-7 miRNA acted as tumor suppressor by repressing the RAS oncogene, growing evidence has suggested the importance of miRNAs targeting the RAS-MAPK in oncogenesis. MiRNAs alterations in human cancers may act as a rheostat of the oncogenic RAS signal that is often amplified as cancers progress. However, specific mechanisms leading to miRNAs deregulation and their functional consequences in cancer are far from being fully elucidated. In this review, we provide an experimental-validated map of RAS-MAPK oncomiRs and tumor suppressor miRNAs from transmembrane receptor to downstream ERK proteins. MiRNAs could be further considered as potential genetic biomarkers for diagnosis, prognosis, or therapeutic purpose.
Highlights
Function of the RAS-Mitogen activated protein kinase (MAPK) signaling pathway is to integrate extracellular signals and coordinate a suitable response by a subsequent control of cellular growth, survival, and differentiation
KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) somatic mutations were identified in more than 90% of pancreatic ductal adenocarcinoma (PDAC) [2]; BRAF and NRAS mutations occur with mutual exclusion in melanoma and account altogether for 83% of the cases [3]; RAS-MAPK signaling pathway is altered in 67% of the T-cell precursor acute lymphoblastic leukemia including mutations in NRAS, KRAS, BRAF, NF1, and PTPN11 [4]; 55% of colon and rectal cancer have alterations in KRAS, NRAS, or BRAF [5]; KRAS, epidermal growth factor receptor (EGFR), NF1, and BRAF mutations occur in 27%, 17%, 11%, and 3% in lung adenocarcinomas, respectively [6, 7]
We can assume that large miRNA families such as let-7 family should be affected by DICER1 and DROSHA somatic mutations
Summary
Binding of the receptor to a ligand induces EGFR dimerization, tyrosine autophosphorylation, and leads to cell proliferation. MiR-219-5p inhibited RAS-MAPK and PI3K pathways in GBM cell lines in concordance with its ability to repress EGFR by directly binding to its 3’UTR This inhibitory effect could be rescued by the overexpression of wild-type EGFR. Forced expression of miR-34a in GBM cells decreased their ability to migrate and potently reduced their proliferation by profoundly decreasing their levels of cyclin-dependent kinase and increased expression of Figure 2: An overview of RAS-MAPK pathway regulation by microRNAs. p21 and p27 cyclin kinase inhibitor proteins. MiR-491-5p efficiently induced apoptosis in ovarian carcinoma IGROV1-R10 cell line by inducing pro-apoptotic BIM accumulation in its dephosphorylated form [31] This effect was due to direct targeting of EGFR by miR-491-5p and consequent inhibition of downstream AKT and RAS-MAPK signaling pathways. The decreased expression of the tumor-suppressive miR-23b/27b cluster enhanced cancer cell proliferation, migration and invasion in bladder cancer through direct regulation of EGFR and MET. Down-regulation of miR-489 and subsequent activation of the RAS-MAPK pathway mediated by an enhanced SHP2 activity could represent a critical oncogenic event in HSCC
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