PVT1: a Rising Star Among Oncogenic Long Noncoding Rnas

Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 304208, 10 pages http://dx.doi.org/10.1155/2015/304208 Review Article PVT1: A Rising Star among Oncogenic Long Noncoding RNAs Teresa Colombo,1 Lorenzo Farina,2 Giuseppe Macino,3 and Paola Paci4 1 Institute for Computing Applications “Mauro Picone”, National Research Council, Via dei Taurini 19, 00185 Rome, Italy 2Department of Computer, Control and Management Engineering, Sapienza University of Rome, Via Ariosto 25, 00185 Rome, Italy 3Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy 4Institute for System Analysis and Computer Science “Antonio Ruberti”, National Research Council, Via dei Taurini 19, 00185 Rome, Italy Correspondence should be addressed to Teresa Colombo; [email protected] Received 16 January 2015; Accepted 12 March 2015 Academic Editor: Anton M. Jetten Copyright © 2015 Teresa Colombo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. It is becoming increasingly clear that short and long noncoding RNAs critically participate in the regulation of cell growth, differentiation, and (mis)function. However, while the functional characterization of short non-coding RNAs has been reaching maturity, there is still a paucity of well characterized long noncoding RNAs, even though large studies in recent years are rapidly increasing the number of annotated ones. The long noncoding RNA PVT1 is encoded by a gene that has been long known since it resides in the well-known cancer risk region 8q24. However, a couple of accidental concurrent conditions have slowed down the study of this gene, that is, a preconception on the primacy of the protein-coding over noncoding RNAs and the prevalent interest in its neighbor MYC oncogene. Recent studies have brought PVT1 under the spotlight suggesting interesting models of functioning, such as competing endogenous RNA activity and regulation of protein stability of important oncogenes, primarily of the MYC oncogene. Despite some advancements in modelling the PVT1 role in cancer, there are many questions that remain unanswered concerning the precise molecular mechanisms underlying its functioning. 1. Introduction are broadly categorized as RNA longer than 200 nucleotides lacking extended open reading frames [11]. Evidence strongly supports pervasive transcription of human While miRNAs have been extensively studied [7–10], genomes, even though only 2% of transcripts encode proteins lncRNAs still constitute a new, potentially fascinating, terri- [1–5]. Noncoding transcripts were for long time regarded tory yet to be explored. Recent studies have begun to associate as evolutionary junk or transcriptional noise, but, with the subsets of lncRNAs to specific regulatory mechanisms [6, 12– development of whole genome technologies, these noncoding 16] of important biological processes, including cell prolif- RNAs (ncRNAs) are emerging as important regulators of gene eration, survival, differentiation, and chromatin remodelling expression. This variegated class of RNA species encompasses both in cis and in trans. Many functional lncRNAs have been the well-known microRNAs (miRNAs), as well as the most shown to play key roles in organ development and cancer; recently acknowledged long noncoding RNAs (lncRNAs). however the biological functions of the majority of lncRNAs Noncoding transcripts are usually classified on the basis largely remain to be identified. Increasing experimental of their size [6]: miRNAs are single-stranded short RNAs evidence supports the hypothesis that lncRNAs may possess (∼22 nucleotides long) that posttranscriptionally regulate competing endogenous RNA (ceRNA) activity [6, 17–21]. gene expression by translation inhibition or degradation of This intriguing mechanism concerns the ability of some theirtargetmRNAs[7–10]; long noncoding RNAs (lncRNAs) RNAs to compete for miRNA binding. 2 BioMed Research International Our group recently developed a computational model 20 able to identify putative ceRNAs among lncRNAs [21]and 18 used it to build normal and cancer networks of miRNA- mediated sponge interactions (MMI-networks). The above 16 ceRNA model, which we applied to breast cancer data from 14 the Cancer Genome Atlas (TCGA) [22], allows characteriza- 12 tion of lncRNAs in terms of oncogenes or tumor-suppressors protagonists in cancer. This speculation was gleaned by the 10 observation of a marked rewiring in the ceRNA program 8 between normal and pathological breast tissues. Most impor- 6 tantly, this analysis fueled our interest in the lncRNA PVT1 as publications of Number being the first hub of the normal-MMI-network. We found 4 that PVT1 favors binding to the crucial mir-200 family as 2 the bone of contention with plenty of competitor mRNAs 0 with declared importance in tumorigenesis since this miRNA 1983 2005 2011 1997 1999 1987 1989 1991 2003 2007 2009 2013 2015 1985 1993 2001 family mediates over 80% of the interactions included in the 1995 PVT1 MMI-subnetwork in normal breast. Number of publications (year) The human PVT1 gene (also known as Pvt1 oncogene) is Figure 1: Rising interest in the oncogenic lncRNA PVT1. Barplot a long intergenic noncoding RNA (lincRNA) homologous to showing the frequency for publications having the word “PVT1” the mouse plasmacytoma variant translocation gene (Pvt1). in the title and/or abstract listed in PubMed http://www.ncbi Indeed this locus has been first discovered in the mid 80s .nlm.nih.gov/pubmed,asofJanuary2015. inmouseasfrequentlyinvolvedinavarianttranslocation in plasmacytomas [23, 24]. Shortly after, the PVT1 locus emerged as a site of variant translocations also in human Burkitt’s lymphomas [25–27]. Around the same years, sys- 2. PVT1 Genomic Locus tematic studies conducted in mice and rats to find common retroviral integration sites in T lymphomas revealed the Pvt1 In humans the chromosomal locus encoding PVT1 gene as one such locus, suggesting its oncogenic potency (Figure 2(a)) maps to band 4 of region 2 on the long arm [28–30]. This oncogenic attitude of PVT1 gained support of chromosome 8 (8q24), specifically to sub-subband 1 of from later evidences of frequent upregulation [21, 31–35]and subband 2 therein (8q24.21). The 8q24 locus has often amplification in a wide variety of cancers. Moreover, PVT1 attracted the attention of researchers for at least three main lies in a recognized cancer risk locus that it shares with reasons: (i) it constitutes a preferred site for genetic aberra- the well-known MYC oncogene. This site, which maps to tions, including translocation [25, 37, 38], amplification chromosome 8 in human, is among the top target of copy [25, 38–41], and viral integration [42, 43] in a wide variety number alterations in cancer and has equivalents in both of cancers and other malignancies (Figure 2(b)); (ii) it mouse (chromosome 15) and rat (chromosome 7) [25, 28, 36, encompasses multiple risk loci for different diseases [44–56]; 37]. and (iii) it includes a 1.8-megabases region of gene desert, In the light of all the above, we can hazard a guess that sotermedduetopaucityoftranscriptionalactivity[57, 58], if PVT1 was a protein-coding gene it would have been at which is considered a cancer risk site likely involved in the heart of countless studies aimed at the functional char- long-range interactions that affect the expression of distant acterization since its discovery. Rather, being a noncoding genes [45, 59, 60]. Indeed, chromosome conformation transcripthasslowedtheprocessofshadinglightonits capture- (3C-) based studies have confirmed extensive phys- mechanisms of action, for reasons of both technical and ical contacts of this risk locus with multiple genomic regions, cultural nature. In the early years of its discovery, in fact, on including intrachromosomal interactions with the PVT1 the one hand the classical molecular techniques for functional locus [60, 61]. investigation were not suited to detecting and analyzing AnotherremarkablefeatureofthePVT1locusistoreside noncoding RNAs; on the other hand it was hardly conceivable some 60 kilobases (kb) 3-prime of the well-known MYC that what was still deemed as transcriptional noise could play oncogene and different functional interactions between these an active role in the regulation of important processes. two genes have been proposed [41, 62]. Adding to this, the Instead, the technological revolution of recent years along MYC-PVT1 pair of genes results syntenic in human (chromo- with the unprecedented appreciation of the multifaceted some 8), mouse (chromosome 15), and rat (chromosome 7) world of noncoding RNAs has led to a renewed interest in (Figure 2(c))[25, 37]. Yet, there is also evidence for indepen- the investigation of the PVT1 function. This growing interest dentcontributionofPVT1andMYCtodisease[31, 60]. isreflectedinthemultitudeofpaperspublishedinthelast Both the mouse and the rat homologous of human PVT1 few years on PVT1 (Figure 1). As a consequence, new inter- (Pvt1 and Mis-1, resp.) constitute sites of frequent retroviral esting hypotheses are emerging on the regulatory networks integration [59, 63–66]and,similarlytothehumancounter- involving PVT1 in normal cells and disease. Nonetheless, the part, sites of frequent translocations in B-cell derived tumors precise mechanism of PVT1 functioning still remains largely

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