Bone marrow stroma-derived miRNAs as regulators, biomarkers and therapeutic targets of bone metastasis

Abstract

MicroRNAs (miRNAs) are short, endogenous RNA molecules that have essential roles in regulating gene expression. They control numerous physiological and cellular processes, including normal bone organogenesis and homeostasis, by enhancing or inhibiting bone marrow cell growth, differentiation, functional activity and crosstalk of the multiple cell types within the bone. Hence, elucidating miRNA targets in bone marrow stromal cells has revealed novel regulations during bone development and maintenance. Moreover, recent studies have detailed the capacity for bone stromal miRNAs to influence bone metastasis from a number of primary carcinomas by interfering with bone homeostasis or by directly influencing metastatic tumor cells. Owing to the current lack of good diagnostic biomarkers of bone metastases, such changes in bone stromal miRNA expression in the presence of metastatic lesions may become useful biomarkers, and may even serve as therapeutic targets. In particular, cell-free and exosomal miRNAs shed from bone stromal cells into circulation may be developed into novel biomarkers that can be routinely measured in easily accessible samples. Taken together, these findings reveal the significant role of bone marrow stroma-derived miRNAs in the regulation of bone homeostasis and bone metastasis. Biogenesis and Function of miRNAsMicroRNAs (miRNAs) are a large family of noncoding B22-nucleotide-long RNA molecules that negatively regulate gene expression. 1 It is estimated that miRNAs regulate about 50% of all protein-coding genes. 2 They repress gene expression through complementary binding to sites in the 3 0 -untranslated region (UTR) of target mRNAs. 3,4 miRNA-mediated inhibition occurs either by mRNA degradation or translational silencing. Cleavage of target mRNAs occurs when the miRNA and the target mRNA exhibit perfect complementarity. 3 Conversely, miRNA-mRNA pairings with imperfect complementarity result in translational inhibition in the absence of target cleavage. 3,5 Thus, even in the absence of perfect binding, the association between an miRNA and a target 3 0 -UTR still results in the suppression of a target protein. Owing to the relatively short length of the seed sequence that binds to the 3 0 -UTR (5-7 nucleotides), each miRNA can potentially recognize hundreds of mRNAs and is thus a powerful molecular manager that can control several gene regulatory networks simultaneously.miRNA genes are typically transcribed into stem-loop structures from intra-or intergenic regions by RNA polymerase II and undergo sequential cleavage steps to produce mature miRNAs. 2 In the nucleus, newly transcribed pri-miRNAs (primary miRNAs) are cleaved by a complex formed by the RNase III enzyme Drosha and the double-stranded RNA-binding protein Pasha (or DGCR8) to produce precursor miRNAs. These precursor miRNAs are about 70-100 nucleotides long. 6 They are exported from the nucleus by Exportin 5 and the Ran-GTP cofactor, 7 where they undergo a second cleavage by the endoribonuclease Dicer to produce a double-stranded, B18-2...

Identification of a novel long noncoding RNA that promotes osteoblast differentiation

“…3,43 On the other hand, our bioinformatics analyses suggest that lncRNA-1 can play a "sponge" role during the initial stages of osteoblast lineage commitment by potentially capturing miR molecules that inhibit this differentiation process (data not shown). Thus, 3 miRs (miR-582, miR-99a, miR-93) that have been recently reported to prevent osteogenic lineage commitment [44][45][46] have the potential to specifically bind sequences included in lncRNA-1. In addition, increased expression of lncRNA-1 from the initial stages of osteoblast differentiation may be contributing toward decreasing the potential of precursor cells to induce adipogenic differentiation.…”