miR-20a and miR-290, multi-faceted players with a role in tumourigenesis and senescence.
Bottom Line: The INK4a/ARF locus which codifies for two proteins, p19ARF and p16INK4a, plays a central role in senescence by controlling both p53 and RB.Intriguingly, both miR-20a, member of the oncogenic miR-17-92 cluster, and miR-290, belonging to the miR-290-295 cluster, are highly expressed in embryonic stem (ES) cells.We propose that miRNAs may exert opposing functions depending on the miRNAs repertoire as well as target/s level/s present in different cellular contexts, suggesting the importance of evaluating miRNAs activity in diverse genetic settings before their therapeutic use as tumour suppressors.
Affiliation: Laboratory of Gene and Molecular Therapy, Institute of Clinical Physiology, CNR, Pisa, Italy.Show MeSH
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Mentions: MicroRNAs (miRNAs) are non coding short 22 nt RNA molecules which have recently come to stage as important players in basic cellular functions such as cell proliferation, differentiation apoptosis and senescence [15, 16]. Interestingly, increasing evidence indicates that many disease states such as cardiovascular, neurodegenerative, liver and kidney diseases  as well as cancer  occur or are sustained by miRNA disregulation. Expression of miRNAs changes markedly in tumours  and an increasing body of evidence indicates that they can behave either as tumour suppressor genes (TS miRNAs) or as oncogenes (onco miRNAs) [19–21], although it is becoming clearer that some miRNAs have a double role (TS and onco miRNAs) according to the cellular context . MiRNAs are negative regulators of gene expression by imperfectly pairing to sequences (named seed match) in the 3′UTR of the target mRNA and inhibiting its translation : thus miRNAs may behave as oncogenes when they inhibit tumour suppressor genes, while their tumour suppressor activity is due to the inhibition of oncogenes (Fig. 1). TS miRNAs, identified as they were markedly under-expressed in tumours, have been shown to play a role both in senescence and in apoptosis (the two main tumour suppressor mechanisms). A list of the most common TS miRNAs as well as of miRNAs with a double behaviour (TS and onco miRNAs) and their relative targets is given in Table 1. It is evident that while few TS miRNAs have been shown to exert a pro-senescence activity, others target well known anti-senescence genes suggesting a possible role in senescence. One of the first discovered TS miRNAs was let-7, down-regulated in various solid tumours [19, 24]. The proto-oncogene RAS was the first validated target of let-7 , but recently let-7 has also been shown to have a role in senescence and aging by targeting a negative regulator of the INK4a/ARF locus, the so-called high-mobility group AT-hook 2 (HMGA2) protein .
Affiliation: Laboratory of Gene and Molecular Therapy, Institute of Clinical Physiology, CNR, Pisa, Italy.