RAS-MAPK pathway epigenetic activation in cancer: miRNAs in action

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.

Keywords: RAS MAPK pathway; cancer; epigenetics; microRNAs.

Figure 1

The canonical miRNA processing pathway includes the production of the primary miRNA transcript (pri-miRNA) by RNA polymerase II and cleavage of the pri-miRNA by the microprocessor complex Drosha in the nucleus. The resulting precursor hairpin, the pre-miRNA, is exported from the nucleus by Exportin-5. In the cytoplasm, the RNase Dicer cleaves the pre-miRNA hairpin to its mature length. The functional strand of the mature miRNA is loaded together with Argonaute (Ago2) proteins into the RNA-induced silencing complex (RISC), where it guides RISC to silence target mRNAs through mRNA cleavage, translational repression, whereas the passenger strand is degraded [15].

Figure 2. An overview of RAS-MAPK pathway regulation by microRNAs