Long non-coding RNAs as novel therapeutic targets in cancer

As a result of the explosion of large-scale genome sequencing projects, we have gained great insights into the evolution of complex organisms. Perhaps, one of the most unexpected outcomes of these studies was that the human genome contains only about 20,000 protein-coding genes, which occupy less than 3% of human DNA. Most of these genes also appear rather well conserved throughout evolution from microscopic worms to men, showing that biological complexity doesn’t quite correlate with the coding part of our genome. These studies clearly outlined that what actually appeared to differ more between simple and complex organisms was the remaining portion of the genome, which was initially thought to be mostly non-functional. As this part of the genome unambiguously aligned with plenty of cDNA sequences coming from the several sequencing efforts that started along with the genome projects, it suggested that this region was not made simply of ‘junk’ or “selfish” DNA. Indeed, it was pervasively transcribed. While it was also argued that this huge amount of transcripts could reflect some sort of transcriptional “noise”, some of them already appeared to have a regulatory function, like for example those that were found to be antisense transcribed in respect to their sense protein genes, suggesting a regulatory mechanism on their function. Data obtained both from microarray tiling experiments and the subsequent massive RNA sequencing technology  confirmed that this ‘dark’ part of our genome contained a plethora of non-coding RNAs (ncRNAs), with most recent data from the ENCODE consortium showing that about 80% of the genome is transcribed. Last, but not least, initial functional experiments on ncRNAs confirmed both their role in embryonic development of complex organisms, exerted by modulating genetic networks and signal transduction pathways, and their poor conservation across species compared to protein coding genes.

ncRNAs have been primarily classified, according to the size of their transcript, into small ncRNAs (less than 200 nt) and long ncRNAs (lncRNAs; more than 200 nt). It should be noted that this rather arbitrary length threshold reflects the size limits of several RNA extraction protocols, and it also allow discriminating between lncRNAs and short and medium ncRNAs, like micro-RNAs (miRNAs), piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and transfer RNAs (tRNAs). Small ncRNAs, especially miRNAs, have been extensively characterized as post-transcriptional regulators of mRNAs and their role in cancer has being increasingly characterized. While evidence for the relevance of lncRNAs in cancer is growing steadily, they are, instead, relatively less characterized both in terms of annotation and comprehension of their mechanism of action. Like many other molecules involved in early embryonic development, lncRNAs seem to also play an important role in cancer. Along this line, a wordcloud, generated using all Pubmed abstracts containing the keywords “lncrna” and “cancer”, identifies, among the most frequent terms, words like “proliferation”, “apoptosis”, “invasion”, “metastasis”, “survival”, “progression”, “prognosis”, etc., further underlining the relevance of lncRNAs in cancer and suggesting for them also a role as a novel class of therapeutic targets. According to this scenario, and since accumulation of lncRNAs in the databases is growing at a steady rate, several of the existing approaches to ablate their function will be likely rapidly exploited to target their function in different tumor types, with some of these approaches probably being even further developed in the clinic.

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Lavorgna G, Vago R, Sarmini M, Montorsi F, Salonia A, Bellone M. (2016) Long non-coding RNAs as novel therapeutic targets in cancer. Pharmacol Res [Epub ahead of print]. [abstract]

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