PVT1: a rising star among oncogenic long noncoding RNAs

Abstract

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.

Figure 1

Rising interest in the oncogenic lncRNA PVT1. Barplot showing the frequency for publications having the word “PVT1” in the title and/or abstract listed in PubMed http://www.ncbi.nlm.nih.gov/pubmed, as of January 2015.

Figure 2

The PVT1 locus in humans. (a) UCSC Genome Browser (http://genome.ucsc.edu/) view of the 8q24.21 region in humans, which contains the PVT1 gene. (b) Barplot of cross cancer alteration frequency for the PVT1 gene. x-axis: different cancer types from the Cancer Genome Atlas [22]. y-axis: total frequency of PVT1 gene alterations. Summary of TCGA cross cancer data and visualization obtained from the cBioPortal for Cancer Genomics (http://www.cbioportal.org/). (c) Sketch of rat and mouse genomic regions syntenic to the human MYC/PVT1 region.

Figure 3

The PVT1 expression in a human atlas. (a–c) Barplots of sorted PVT1 expression values across human cell lines, tissues, and primary cells, respectively. Expression data are taken from the atlas recently released by the FANTOM consortium [71]. y-axis: normalized expression value (tags per million). x-axis: human cell lines, tissues, and primary cells, respectively. In each panel, the name of the top 20 samples is listed and the corresponding bars are similarly colored. In (a), the inset shows the overall sorted PVT1 expression values in human cell lines. The PVT1 expression data plotted in (a–c) (i.e., 186 cell lines, 113 tissues, and 136 primary cells) constitute a subset of the full FANTOM atlas (>850 samples) that was selected to reduce redundancy in the plots. (d) Scatterplot of the MYC versus PVT1 expression values across all the samples analyzed in (a–c). The Pearson correlation (r) and the corresponding P value are shown.

Figure 4

PVT1 expression in cancer. (a) Barplots of mean PVT1 expression in cancer versus normal tissues from the Cancer Genome Atlas [22]. Values are ordered by decreasing abundance in cancer. y-axis: normalized expression value (FPKM). x-axis: TCGA tissues. (b) Barplots of mean PVT1 expression in TCGA cancer tissues, ordered by decreasing abundance. x-axis and y-axis: same as in (a). (c) Scatterplot of the MYC versus PVT1 expression values across all the samples analyzed in (a-b). The Pearson correlation (r) and the corresponding P value are shown. Abbreviations: acc: adrenocortical carcinoma; blca: bladder urothelial carcinoma; lgg: brain lower grade glioma; brca: breast invasive carcinoma; cesc: cervical squamous cell carcinoma and endocervical adenocarcinoma; chol: cholangiocarcinoma; coad: colon adenocarcinoma; gbm: glioblastoma multiforme; hnsc: head and neck squamous cell carcinoma; kich: kidney chromophobe; kirc: kidney renal clear cell carcinoma; kirp: kidney renal papillary cell carcinoma; lihc: liver hepatocellular carcinoma; luad: lung adenocarcinoma; lusc: lung squamous cell carcinoma; dlbc: lymphoid neoplasm diffuse large B-cell lymphoma; meso: mesothelioma; ov: ovarian serous cystadenocarcinoma; paad: pancreatic adenocarcinoma; pcpg: pheochromocytoma and paraganglioma; prad: prostate adenocarcinoma; read: rectum adenocarcinoma; sarc: sarcoma; skcm: skin cutaneous melanoma; tgct: testicular germ cell tumors; thym: thymoma; thca: thyroid carcinoma; ucs: uterine carcinosarcoma; ucec: uterine corpus endometrial carcinoma; uvm: uveal melanoma.

Figure 5

The PVT1 functions. (a) Model of PVT1 ceRNA mechanism operating in normal breast but not in breast cancer tissues possibly due to a prevalence in cancer of expression of PVT1 isoforms lacking recognition elements for the miRNA to be sponged, as it has been hypothesized for the case of mir-200 family based on sequence analysis of alternative PVT1 isoforms [21]. (b) Model of PVT1 positive regulation of the MYC protein stability by rescuing MYC from phosphorylation [87]. This figure is inspired by [87]. (c) The proposed model of TGFβ1/PVT1/NOP2 regulatory network [41]: TGFβ1 promotes the interaction between PVT1 and NOP2 that in turn activates proliferation, cell cycle, and TGFβ signalling pathways. The sketches of yellow switches in the figure symbolize the pathway activation.