Micro-RNAs as diagnostic or prognostic markers in human epithelial malignancies

Abstract

Micro-RNAs (miRs) are important regulators of mRNA and protein expression; the ability of miR expression profilings to distinguish different cancer types and classify their sub-types has been well-described. They also represent a novel biological entity with potential value as tumour biomarkers, which can improve diagnosis, prognosis, and monitoring of treatment response for human cancers. This endeavour has been greatly facilitated by the stability of miRs in formalin-fixed paraffin-embedded (FFPE) tissues, and their detection in circulation. This review will summarize some of the key dysregulated miRs described to date in human epithelial malignancies, and their potential value as molecular bio-markers in FFPE tissues and blood samples. There remain many challenges in this domain, however, with the evolution of different platforms, the complexities of normalizing miR profiling data, and the importance of evaluating sufficiently-powered training and validation cohorts. Nonetheless, well-conducted miR profiling studies should contribute important insights into the molecular aberrations driving human cancer development and progression.

Figure 1

Micro-RNA biogenesis. MiR's are synthesized initially as large RNA precursors (pri-miRs), processed in the nucleus by RNAse III Drosha, and DGCR8 into approximately 70 nt pre-miR, which are transported to the cytoplasm by exportin-5, with subsequent cleavage by another RNAse III enzyme Dicer, with its co-factor TRBP, releasing the approximately 22-nt mature dsmiR. MiR's can negatively regulate their targets in one of two major ways, depending on the degree of complementarity to its target. First, and probably most commonly, one strand of this duplex is incorporated into the RNA-induced silencing complex (RISC), then binds with imperfect complementarity to the 3'-UTR (untranslated region) of mRNA targets, preventing protein translation. Alternatively, miRs can bind with perfect complementarity to the ORF (open reading frame) of target mRNA's with subsequent degradation. Recent evidence also indicates miRs can also bind to either promoters, or coding regions of mRNAs as additional mechanisms of regulation.