Intertwined roles of microRNA-155 and metformin in osteoarthritis: Novel potential diagnostic, prognostic, and therapeutic modulators

Figure 1 The regular microRNA biogenesis process. Schematic representation of microRNA-155 (miR-155) biogenesis. MIR155HG is transcribed in the nucleus by an RNA polymerase II (RNA pol II) to a primary miR-155 (pri-miR-155). This pri-miR-155 will be processed further by the Drosha-DiGeorge syndrome critical region gene 8 (microprocessor) complex in the nucleus to produce a 65-nucleotide stem-loop precursor miRNA (pre-miR-155). Exportin-5 exports the pre-miR-155 from the nucleus to the cytoplasm where it will be processed by the RNase III enzyme, Dicer, resulting in RNA duplexes of 22 nucleotides, the miR-155-5p and miR-155-3p. After Dicer cleavage, an Argonaute protein binds short RNA duplexes to form the core of the RNA-induced silencing complex (RISC) that incorporates the mature miR-155. Once bound to RISC the guide strand is retained and functional while the other (passenger strand) is degraded. The RISC/guide strand-mature miR-155 complex can now seek and recognize its target messenger RNAs and bind to it/them through complementary base pairing interactions on their 3′-UTR and its seed region (nucleotides 2 to 8) on the 5’UTR leading to translational repression and/or degradation. MIR155HG also encodes a long noncoding RNA-155 involved in the regulation of antiviral innate immunity and can function as a competing endogenous miRNA sponging and downregulating other miRNAs. Ago: Argonaute; DGCR8: Drosha-DiGeorge syndrome critical region gene 8; lncRNA-155: Long noncoding RNA-155; miR-155: MicroRNA-155; mRNA: Messenger RNA; RISC: RNA-induced silencing complex; RNA pol II: RNA polymerase II; TRBP: The human immunodeficiency virus transactivating response RNA-binding protein.