‘microRNA’ Review Series The ongoing microRNA revolution and its impact in biology and medicine

Abstract

‘microRNA’ Review Series First identified more than a decade ago in C. elegans, microRNAs have emerged as key molecular players in virtually all the cellular processes studied to date [1]. The scientific community has witnessed an arguably unparalleled expansion in the number of publications focusing on microRNA biology, from only a handful in 2001 to well over a thousand during the course of last year. In the meantime, the number of experimentally confirmed microRNAs has increased, now exceeding 500 in most studied organisms, including mammals. Many microRNAs exhibit a remarkable degree of evolutionary conservation between birds, rodents and primates, a reflection of their critical importance for fundamental cellular processes. Novel bioinformatic approaches and increasingly advanced cloning technologies could lead to a further enrichment of the microRNAs world in the years to come. Mechanistically, microRNAs interfere with gene expression at post-transcriptional level, subsequently to base pairing to partially complementary sites within the 3'UTR of the targets [2]. The early prevailing paradigm divided microRNAs actions along evolutionary lines. Thus, in plants they were thought to interfere with messenger RNA stability, similar to siRNAs, whereas in animal cells inhibition of protein translation was proposed to be their dominant, if not the exclusive, action. More recently, however, this dichotomy has been challenged by experimental data, as mRNA degradation seems relatively common in mammalian cells [3]. Another amendment to the translation inhibition paradigm was issued last year, with the identification of specific microRNAs that enhance rather than inhibit translation of specific protein. For example, miR-369–3 was shown to stimulate the translation of tumour necrosis factor-α during cell cycle arrest, contrary to its effect in proliferating cells [4]. It is entirely possible that this case represents only the tip of the iceberg, and under specific circumstances a multitude of microRNAs could switch between inhibition and stimulation of protein translation. In parallel to the rapid gain in biological knowledge, the commercially available technology has matured, as multiple life-science companies (such as LC sciences; Houston, TX, USA, Ambion, Inc (now part of Applied Biosystems); Austin, TX, USA, Exiqon; Vedback, Denmark, Invitrogen; Carlsbad, CA, USA) now provide a wide range of reagents and microarray platforms. Profiling approaches have started to shed light into the dynamic of the ‘microtranscriptome’ in diverse processes, such as development, metabolic processes or signalling. Additionally, signatures for a wide variety of diseases have been generated, leading the way to more focused investigations into the roles of specific microRNAs. Arguably the most extensive effort has been undertaken in cancer, one important outcome being microRNA signature(s) attached to virtually every major tumour type [5]. Similar to the case of ‘classic’ genes, oncogenic and tumour-suppressing microRNAs have been identified, which directly regulate apoptosis and/or cell cycle, and in some cases undergo mutations in specific malignancies. Additionally, some cancer-relevant microRNAs have been shown to respond to cellular stresses such as hypoxia, and are thought to play critical roles in cellular adaptation to these [6, 7]. Mechanistic studies of microRNAs have met challenges that are not encountered during the functional dissection of translated genes. This stems from the relative promiscuity of microRNA-dependent gene targeting, characterized by tens or even hundreds of predicted targets, with only partial overlap between the various prediction programs (PicTar, TargetScan, Miranda, etc.). A major step forward has been constituted by the development of animal models that open the way for in vivo investigation of microRNA roles in physiology and pathology. For example, the first transgenic mouse overexpressing miR-155 in B-lymphocytes turned out to be a powerful model of haematological malignancies that naturally overexpress this microRNA (Hodgkin lymphomas, B cell and Burkitt lymphomas) [8]. Conversely, mir-155 gene knockouts developed a wide dysfunction of the immune response, involving T, B and dendritic cells [9]. The involvement of microRNAs in disorders that sit at the top of morbidity and mortality lists (cancer, inflammation, and possibly, cardiovascular pathology and stroke [10]) can be viewed as an opportunity for novel therapeutic approaches. Along these lines, progress has been achieved for the targeting of select disease-relevant microRNAs, with several drug candidates making promising strides in clinical trials [11]. The plethora of exciting developments in the microRNA field, from basic science to translational applications, serve as fertile background for the review series hosted by the Journal of Cellular and Molecular Medicine. It is also an opportunity to wholeheartedly invite researchers from the field and beyond to contribute to the journal with novel angles to this fast-evolving area.