MicroRNAs: regulators of oncogenesis and stemness

With over 500 microRNA (miRNA) genes identified experimentally in the human genome and a plethora of computationally predicted mRNA targets, it is believed that these small non-coding RNAs have a central role in diverse cellular and developmental processes. miRNAs function as endogenous triggers of the RNA interference pathway. When mature (active) they are ~22 nt small RNAs, generated by two cleavage steps, which are catalyzed by two distinct complexes: Drosha, which is found in the nucleus, and Dicer, which is found in the cytoplasm (Figure 1) [1]. Following Dicer cleavage, the mature form of the miRNA is incorporated into the RNA-induced silencing complex (RISC) where the 3' untranslated region (3'-UTR) of the target mRNA associates with the major component of the RISC complex, Argonaute (Figure 1) [1].miRNAs act on cellular transcripts by two different mechanisms. The first mechanism is cleavage-dependent RNA degradation of the transcript at the site where the miRNA binds. The other mechanism is miRNA-mediated translational repression of the target transcript, while the miRNA binds to the target 3'-UTR with several mismatches. This partial complementarity allows for miRNAs to target multiple 3'-UTRs [1]. A key question that arises from the targeting of multiple transcripts is whether there has been evolutionary enrichment in targets that are involved in similar cellular functions.Aberrant expression of miRNA genes can lead to human diseases, including cancer. In recent years, a number of informative profiling studies have determined the levels of miRNAs in various types of cancer cell lines and tumors [2]. Most of these studies have identified multiple dysregulated miRNAs, which in many cases can classify cancer types [3]. In addition, multiple functional studies on tumor suppressive or oncogenic miRNAs were identified from profiling, screens or due to their cancer-associated genomic loci [2,3].The first tumor suppressive miRNAs identified were the miR-15/miR-16