REVIEW published: 06 November 2019 doi: 10.3389/fonc.2019.01173 Long Non-coding RNA PVT1 as a Prognostic and Therapeutic Target in Pediatric Cancer Ariadna Boloix 1,2,3 , Marc Masanas 1 , Carlos Jiménez 1 , Roberta Antonelli 1 , Aroa Soriano 1 , Josep Roma 1 , Josep Sánchez de Toledo 1 , Soledad Gallego 1 and Miguel F. Segura 1* 1 Group of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 2 Institut de Ciència de Materials de Barcelona (ICMAB-CSIC), Esfera UAB, Cerdanyola del Vallès, Spain, 3 CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain In recent decades, biomedical research has focused on understanding the functionality of the human translated genome, which represents a minor part of all genetic information transcribed from the human genome. However, researchers have become aware of the importance of non-coding RNA species that constitute the vast majority of the transcriptome. In addition to their crucial role in tissue development and homeostasis, mounting evidence shows non-coding RNA to be deregulated and functionally contributing to the development and progression of different types of human disease including cancer both in adults and children. Small non-coding RNAs (i.e., microRNA) are in the vanguard of clinical research which revealed that RNA could Edited by: be used as disease biomarkers or new therapeutic targets. Furthermore, many more Heather Cunliffe, expectations have been raised for long non-coding RNAs, by far the largest fraction University of Otago, New Zealand of non-coding transcripts, and still fewer findings have been translated into clinical Reviewed by: Sarah D. Diermeier, applications. In this review, we center on PVT1, a large and complex long non-coding University of Otago, New Zealand RNA that usually confers oncogenic properties on different tumor types. We focus on Kavitha Yaddanapudi, University of Louisville, United States the compilation of early advances in the field of pediatric tumors which often lags behind *Correspondence: clinical improvements in adult tumors, and provide a rationale to continue studying Miguel F. Segura PVT1 as a possible functional contributor to pediatric malignancies and as a potential miguel.segura@vhir.org prognostic marker or therapeutic target. Specialty section: Keywords: PVT1, lncRNA, epigenetic, 8q32, pediatric cancer This article was submitted to Cancer Genetics, a section of the journal PEDIATRIC CANCER Frontiers in Oncology Received: 25 March 2019 Pediatric cancers are rare diseases which differ from adult malignancies owing to their etiology, Accepted: 18 October 2019 biology, response to treatment, and outcome. The most frequent adult cancers are of epithelial Published: 06 November 2019 origin and, in some cases, are caused by environmental factors. By contrast, pediatric tumors tend Citation: to be of hematologic, mesenchymal, or nervous system origin and their etiology is often little known Boloix A, Masanas M, Jiménez C, (1). Approximately 160,000 cases of cancer in children and adolescents are diagnosed every year Antonelli R, Soriano A, Roma J, worldwide, accounting for up to 2% of all cancers (2). In recent decades, with the introduction of Sánchez de Toledo J, Gallego S and multimodal treatments, the outcome of children and adolescents has improved, reaching ∼80% of Segura MF (2019) Long Non-coding RNA PVT1 as a Prognostic and overall survival. Despite this significant improvement, cancer remains the leading cause of death Therapeutic Target in Pediatric in children, and adolescents worldwide (3). Furthermore, two thirds of patients may suffer severe Cancer. Front. Oncol. 9:1173. side effects associated with these intensive treatments (4). Thus, the development of safe and more doi: 10.3389/fonc.2019.01173 effective therapies is a must. Frontiers in Oncology | www.frontiersin.org 1 November 2019 | Volume 9 | Article 1173 Boloix et al. PVT1 in Pediatric Cancer LNCRNAS AND CANCER the P53 transcriptional response (20). Furthermore, lncRNAs may also regulate mRNA stability and translation processes. For The Emerging Opportunity of Long instance, the TMPO-AS1 lncRNA regulates the expression of Non-coding RNAs (LncRNAs) Thymopoietin, a protein involved in the maintenance of the Current therapies are directed at targeting the functionality of nuclear envelope structure. Qin et al. demonstrated that the the human translated genome (i.e., proteins), barely 2% of all knockdown of TMPO-AS1 also resulted in a decrease of TMPO transcribed genetic information (5). Therefore, use of the largest mRNA and protein levels (21). part of the transcribed genome for therapeutic, diagnostic, and However, one of the most described roles of lncRNAs in prognostic purposes remains unexplored (6). Recent advances in cytoplasm is microRNA (miRNA) sequestration. LncRNAs may high-throughput sequencing technologies have been crucial for contain multiple miRNA binding sites and can sequester them, improving understanding of non-coding RNA (ncRNA), which thereby reducing their availability for their target genes (22). represents a significant fraction of all transcribed RNAs, and in In particular, lncRNAs may regulate the expression of a certain the past, were considered evolutionary junk or transcriptional mRNA by having a miRNA recognition element (MRE) in its noise (7, 8). However, ncRNA are now known to be important sequence. This competition for a miRNA gives name to the regulators of biological processes such as gene expression (9). competing endogenous RNA (ceRNA) hypothesis formulated by Furthermore, interest in ncRNAs has grown owing to their Salmena et al. (23). One of such examples is the lncRNA FER1L4, implication in different diseases, such as cancer (6, 10). which modulates PTEN expression by sponging miR-106a-5p in In general, ncRNAs are classified according to their length as gastric (24) or in colon cancer (25). small ncRNAs (sncRNAs) or long ncRNAs (lncRNAs), smaller LncRNAs present evolutionarily-conserved secondary than 200 nt and larger than 200 nt, respectively (11). structure and function, although their exon sequence is much less conserved than protein-coding genes (8, 26). LncRNAs Functions of LncRNAs have been reported to present tissue-specific expression and LncRNAs functionality depends on their subcellular distribution their deregulation has been associated with cancer development, (12). LncRNAs located in the nucleus can regulate gene metastasis, and patient outcome (13) often by regulating expression at different levels: (a) LncRNAs can interact with oncogenes or tumor suppressors. transcription factors or chromatin-remodeling complexes to For example, one of the most studied lncRNAs is the Hox regulate gene expression in cis, i.e., when the lncRNAs locus transcript antisense intergenic RNA (HOTAIR). HOTAIR, has is proximal to the regulated gene, or in trans, when the gene been shown to be overexpressed in multiple human tumors such affected and lncRNAs are at distant locations of the genome as breast, pancreatic, liver, lung, and hepatocellular cancer among (13). For example ANRIL is a lncRNA that interacts with others, and has been involved in different hallmarks of cancer (6, the polycomb repressive complex-1 (PRC1) and−2 (PRC2) 27). Mechanistically, HOTAIR acts as a scaffold for the chromatin and mediates transcriptional silencing of INK4b-ARF-INK4a repressors polycomb repressor complex 2 (PRC2) and histone locus. Specifically, ANRIL binds to Suz12 to recruit PRC2 lysine-specific demethylase 1 (LSD1) and may perform a cis and complex which initiates H3K27me3, a post-translational histone trans-regulation of HOX genes and HOXD cluster, respectively mark indicative of transcriptional repression (14); (b) LncRNAs (28). While the bibliography is abundant for tumors in adult may bind directly to DNA, causing chromatin remodeling or patients, examples are scant in the field of pediatric cancer. One looping, where the lncRNAs can recruit chromatin modifiers such example is the lncRNA neuroblastoma-associated transcript (e.g., histone methyltransferases, DNA methyltransferases) to 1 (NBAT-1) which was associated with good prognosis in enhance or repress gene transcription (15). In fact, there are high-risk neuroblastoma patients (29). Mechanistically, NBAT-1 evidence of sequence-specific interactions of lncRNAs with epigenetically controls the expression of target genes involved in DNA via triple-helix (triplex) formation, a structure that allows cell proliferation, differentiation and cell invasion by interacting lncRNAs to recruit protein complexes to specific genomic regions with EZH2, a subunit of PRC2 (29). and regulate gene expression. For example, the GATA6-AS lncRNA regulates the expression of several genes related to cardiac development using this mechanism (16); (c) finally, other PLASMACYTOMA VARIANT functions of lncRNAs such as their participation in splicing TRANSLOCATION 1 (PVT1) and export or translation of mRNA have also been described (17). One of these examples is the lncRNA Fas-antisense or One of the lncRNAs that is attracting attention in both pediatric Saf, which interacts with Fas receptor pre-mRNA and with the and adult tumors is the plasmacytoma variant translocation 1 human splicing factor 45 (SPF45) in the nucleus of the cell. As (PVT1). Initially described in the middle 80’s, this gene was a consequence, the exclusion of exon 6 from the Fas mRNA is identified as a breakpoint site in chromosome 6;15 translocations, produced. The resulting protein product is a soluble Fas that which are associated with murine plasmacytomas (30). In protects cells against FasL-induced apoptosis (18). humans, this kind of translocation occurs in rare variants of When lncRNAs are in cytoplasm, they can interact with Burkitt’s lymphoma (31). Herein, we focus on this complex and proteins, thereby either activating or inhibiting its function multi-functional lncRNA to raise awareness and pave the way (19). For example, lincRNA-21 is able to interact with the toward better characterization of its use as a potential prognostic Heterogeneous Nuclear Ribonucleoprotein K, and modulates marker or therapeutic target in pediatric cancer. Frontiers in Oncology | www.frontiersin.org 2 November 2019 | Volume 9 | Article 1173 Boloix et al. PVT1 in Pediatric Cancer Conversely, ectopic expression of PVT1 increased trophoblastic cell proliferation (44). In following steps of embryonic development, PVT1 has also been shown to play a significant role in neuronal differentiation. Apparently, PVT1 expression is high in pluripotent stem cells, whereas it decreases during neuronal differentiation (45). Functional Role of PVT1 in Cancer Several studies reported that PVT1 is overexpressed in a wide variety of cancers compared to non-tumoral tissues, including breast and ovarian cancer (46), pancreatic ductal adenocarcinoma (47), cholangiocarcinoma (47), thyroid carcinoma (47), malignant pleural mesothelioma (47), pediatric malignant astrocytoma (46), acute myeloid leukemia (46), and FIGURE 1 | Graphical representation of the 8q24 genomic locus. Hodgkin’s lymphoma (46). Less evidence, however, also supports a potential role of PVT1 as a tumor suppressor (48). PVT1 may impact on tumor biology through different mechanisms: PVT1 Gene Structure “Plasmacytoma variant translocation 1” or PVT1 is a long Role of the miRNA Cluster intergenic ncRNA encoded in the human PVT1 gene (Figure 1). PVT1 encodes a cluster of five miRNA (miR-1204, miR-1205, PVT1 gene is located at the chromosomal locus 8q24.21 which miR-1206, miR-1207, and miR-1208) (34) which have been contains the MYC oncogene. This region is frequently altered shown to play both oncogenic and tumor-suppressive roles. For in many types of cancer owing to chromosomal translocations, example, miR-1204 has been shown to be overexpressed and amplifications or deletions, single nucleotide polymorphisms associated with poor prognosis in breast cancer (BC). The ectopic (SNP) and/or viral integrations (32, 33). The PVT1 gene contains expression of miR-1204 promoted proliferation, epithelial to nine exons, which produce multiple transcripts between 2.7 and mesenchymal transition and invasion of BC cells by targeting 3.3 kb in length by alternative splicing (32). Thus, far, none of the vitamin D receptor (49). MiR-1204 was also shown to these transcripts have been shown to be translated into a protein promote cell proliferation in different types of cancer such product (32). as ovarian squamous cell carcinoma (50), non-small cell lung In addition to these splicing variants, PVT1 contains a cluster cancer (51), or in hepatocellular carcinoma (52). In line with of five different microRNA (i.e., miR-1204, miR-1205, miR- these results, miR-1205 expression was found to be increased in 1206, miR-1207, and miR-1208) which are encoded in the primary prostate tumors and castration-resistant prostate cancer intronic regions of PVT1, except miR-1204, which is located in cell lines. Functional analyses revealed that miR-1205 induced exon 1b (32, 34). Furthermore, PVT1 encodes a circular RNA, cell proliferation and cell cycle progression (53). Concurring which is presented as a covalent closed loop structure without with these results, miR-1205 inhibition impaired osteosarcoma polyadenylated tail (35, 36). This structure, indeed, also has proliferation in vitro and in vivo by suppressing Wnt/β-catenin the capacity to sequester miRNAs such as miR-497 (37, 38) or activation (54). Overexpression of miR-1207-5p has been shown miR-125 (39, 40). to promote cancer stem cells traits in ovarian cancer cells by targeting inhibitors of the Wnt/β-catenin pathways (55) and induce breast cancer cell proliferation by targeting STAT6 (56). PVT1 Participates in Embryonic Conversely, tumor suppressive roles for some of these Development miRNAs have also been reported. For example, ectopic Pediatric cancers are frequently originated in developing expression of miR-1205 significantly inhibited tumor growth organs where the integration of multiple signaling pathways in NSCLC mouse xenograft by targeting MDM4 and E2F1. In related to proliferation, growth factor signaling, developmental addition, multiple circRNA have been suggested to sponge miR- angiogenesis and programmed cell death, take place (41). It is 1205 in glioma (57–59) and papillary thyroid cancer (60) to in this scenario where lncRNA such as PVT1 become critical for increase oncogenicity of these tumors. MiR-1207-5p inhibition proper physiologic development (42). One of such examples is a induced stem phenotype and expression of stem cell markers, recent report showing that PVT1 is involved in the early stages such as OCT4, C-MYC, and SOX2, in nasopharyngeal cancer of development, such as pre-implantation and oocyte maturation (61). MiR-1207-5p also has shown to reduce cell invasion in vitro (43). Moreover, the loss of PVT1 function may also be implicated and metastasis in a lung cancer mouse xenograft model (62). in human disease. For example, PVT1 expression was found to be significantly lower in pregnant women with preeclampsia PVT1-MYC Interaction than that in women with normal pregnancies. Loss of function The proximal location between the well-established oncogene experiments in trophoblast cell lines showed that PVT1 silencing MYC and PVT1 in the 8q24 region prompted researchers resulted in cell proliferation inhibition and apoptosis induction. to analyze whether this lncRNA may somehow regulate or Frontiers in Oncology | www.frontiersin.org 3 November 2019 | Volume 9 | Article 1173 Boloix et al. PVT1 in Pediatric Cancer TABLE 1 | Examples of PVT1-interacting microRNAs. Type of cancer Effects of PVT1 silencing MiRNA Targets References Bladder cancer ↓ Tumor growth miR-31-5p CDK1 (70) ↓ Tumor growth miR-128-3p VEGFC (71) Cervical cancer ↑ Cell apoptosis miR-195-5p SMAD3 (72) Colorectal cancer ↓ Tumor growth miR-455-5p RUNX2 (73) ↓ Cell proliferation, invasion, and migration miR-26b - (74) ESCC ↓ Tumor growth miR-203a-3p LASP1 (75) Hepatocellular carcinoma ↓ Tumor growth miR-150-5p HIG2 (76) - miR-365-3p ATG3 (77) ↓ Cell proliferation and invasion miR-186-5p YAP1 (78) HUVEC* ↓ Cell migration miR-26b-5p ANGPT2 and CTGF (79) Gallbladder cancer ↓ Cell proliferation and invasion miR-143-3p HK2 (80) Gastric cancer - miR-152-3p CD151, FGF2 (81) - miR-216a-5p YBX1 (82) ↓ Cell proliferation and migration miR-186-5p - (83) Glioma ↓ Tumor growth miR-190a-5p MEF2C (84) ↓ Tumor growth miR-488-3p ↓ Invasion and migration miR-200a-3p - (85) ↓ Tumor growth miR-128-3p GREM1 (86) ↓ Cell proliferation miR-186-5p - (87) Lung cancer ↓ Cell proliferation miR-126-3p SLC7A5 (88) LSCC ↓ Cell proliferation and migration miR-519d-3p - (89) Melanoma ↓ Cell proliferation miR-26b-5p - (90) NSCLC ↓ Tumor growth miR-195-5p - (91) ↓ Tumor growth miR-497-5p - (92) ↓ Cell proliferation miR-200a-5p MMP9 (93) miR-200b-5p - miR-216b Beclin 1 (94) ↓ Cell proliferation and invasion miR-125b-5p E2F2 (40) Osteosarcoma ↓ Tumor growth miR-195-5p - (95) ↑ Chemoresistance to gemcitabine miR-152-3p c-MET (96) ↓ Cell proliferation miR-497-5p HK2 (97) Ovarian cancer ↓ Cell proliferation, invasion, and migration miR-133a-3p - (98) ↓ Cell proliferation miR-140-5p - (99) Pancreatic cancer - miR-488-3p - (100) ↓ Cell proliferation, invasion and migration miR-448 SERBP1 (100) ↓ Tumor growth miR-20a-5p ULK1 (101) PTC ↓ Cell proliferation and invasion miR-30a-5p IGF1R (102) Prostate cancer ↓ Cell proliferation and migration miR-186-5p Twist1 (103) Renal cell carcinoma ↓ Cell proliferation and invasion miR-16-5p - (104) Retinoblastoma ↓ Tumor growth miR-488-3p Notch2 (105) ESCC, Esophageal squamous cell carcinoma; LSCC, Laryngeal squamous cell carcinoma; NSCLC, Non-small cell lung cancer; PTC, Papillary thyroid carcinoma; HUVEC, Human umbilical vein endothelial cells. * Indicates that experiments were performed in non-tumoral human cell lines. be regulated by MYC, a master regulator of cell growth, the nucleus and inhibits its degradation by blocking MYC proliferation, and differentiation, widely implicated in cancer phosphorylation at threonine 58 (65). Moreover, stabilized MYC (47). In fact, genomic co-amplification of MYC and PVT1 protein can activate a positive feedback loop, thereby activating has been reported in different types of tumor (63). The first PVT1 expression. Hence, MYC and PVT1 enhance each other’s evidence found for the interaction between these two molecules oncogenic effects (65). Concurring with these observations, was reported by Carramusa et al. who found that PVT1 can siRNA-mediated silencing of PVT1 resulted in a reduction in be transcriptionally regulated by MYC proteins (64). Further MYC protein levels in different tumor types such as colorectal in depth studies revealed that PVT1 interacts with MYC in carcinoma, breast, and ovarian cancer (33). Another level of Frontiers in Oncology | www.frontiersin.org 4 November 2019 | Volume 9 | Article 1173 Boloix et al. PVT1 in Pediatric Cancer regulation is also possible, since MYC can be targeted by miR- 1205, one of the miRNA encoded in the PVT1 RNA (66). Other authors, however, suggested that the oncogenic activities of MYC and PTV1 are independent of each other (67). PVT1 as a Mediator of the Tumor Suppressor Role of p53 Since p53 modulates the expression of several coding and non- coding genes, Barsotti et al. analyzed a potential relationship between p53 and PVT1. Experimental evidence demonstrated that PVT1 contains several p53-binding elements and that certain stress-inducing agents such as DNA-damaging drugs, induced p53-dependent expression of PVT1. The authors went further and found mature levels of miR-1204 to be raised after p53 activation and that it was one of the mediators of the tumor- suppressive functions of p53 in colon cancer cell lines (46). PVT1 as a Competing Endogenous RNA (ceRNA) ceRNA are transcripts that may contain multiple miRNA binding sites (alternatively known as mRNA response elements) that regulate gene expression by sequestering miRNA which otherwise would be bound to their target mRNA. Several studies FIGURE 2 | PVT1 expression comparing healthy tissues (green) with pediatric reported that ceRNA are key regulators of cancer progression (68, tumors (blue). PVT1 RNA expression levels were obtained from 69). Several miRNA have been reported to interact directly with publicly-available Affymetrix expression array (u133p2) datasets using the “R2: PVT1 in different cancers (Table 1) and, importantly, restoration Genomics Analysis and Visualization Platform” software. B cells (GSE12366), of miRNA levels partially rescues the oncogenic effect of PVT1 brain (GSE11882), muscle (GSE9103), colon (GSE8671), Ewing sarcoma overexpression (40, 102). (GSE34620), burkitt lymphoma (GSE26673), mantle cell lymphoma (GSE93291), rhabdomyosarcoma (GSE66533), ALL (GSE68720), neuroblastoma (GSE16476), osteosarcoma (GSE14827), ATRT (GSE70678), PVT1 AND PEDIATRIC CANCER wilm’s tumor (R2 ID: ps_avgpres_wilmsocg125_u133p2), ependymoma (GSE64415), glioma (GSE19578), medulloblastoma (R2 ID: ps_avgpres_mb500affym223_u133p2). a.u, Arbitraty units. Very little is known on the molecular mechanisms that could alter PVT1 expression in pediatric tumors. While genetic aberrations at the 8q24 locus could be responsible for deregulated PVT1 levels in adult malignancies, few cases have been described in pediatric tumors. For example, recurrent translocations of PVT1- Prognostic Value of PVT1 in Pediatric MYC or PVT1-NDRG1 were identified in a large study on Cancer medulloblastoma, the most malignant brain tumor in children While mounting evidence suggests that PVT1 could be a (106), or genomic amplifications of MYC/PVT1 in pediatric prognostic marker in several adult malignancies (110), very few gliomas (107). Additional genetic alterations have been reported analyses have been carried out in pediatric tumors. Indeed, Song in the St. Jude PeCAn Data Portal. The analysis of the PVT1 gene et al. analyzed PVT1 expression in osteosarcoma (OS), the most in a cohort of 3,769 pediatric cancer samples from the projects common malignant bone tumor in children, adolescents and PCGP (St. Jude-WashU Pediatric Cancer Genome Project) (108) young adults. The authors found PVT1 to be overexpressed in and TARGET (Therapeutically Applicable Research to Generate OS cell lines and in tumor samples compared with healthy tissue. Effective Treatments) (109) reveals 62 different intronic single Furthermore, high PVT1 RNA levels correlated with poor overall nucleotide variants and small insertions and deletions, 8 copy survival (97). neutral loss of heterozygosity, 50 copy number variants, 43 DNA In line with these observations, we sought to determine structural variants, and 6 RNA-seq fusions. However, the clinical whether PVT1 could also be a prognostic marker in other relevance of these alterations remains to be determined. pediatric cancers. Data mining of publicly-available databases Regardless of these examples, transcriptomic analysis of PVT1 which contain PVT1 expression along with annotated clinical showed it to be expressed in different pediatric tumors, with parameters was performed for wilm’s tumor (n = 148, R2 higher levels corresponding to hematologic malignancies and ID:ps_avgpres_wilmsocga148_u133a), neuroblastoma (n = 476, sarcoma, and more moderate expression in nervous system GSE45547), mantle cell lymphoma (n = 122, GSE93291), tumors (Figure 2), thereby suggesting that PVT1 has the ewing’s sarcoma (n = 52, GSE17679), osteosarcoma (n = potential to be used as a prognostic marker or as a therapeutic 88, GSE42352), and pediatric glioma (n = 47, SE19578), target in some pediatric tumors. Further studies, however, are and revealed that, in neuroblastoma, the expression of PVT1 needed to reveal the mechanism(s) controlling PVT1 expression could have prognostic value (Figure 3). In addition to PVT1 in childhood tumors. full RNA, other authors used circular RNA (circRNA) of Frontiers in Oncology | www.frontiersin.org 5 November 2019 | Volume 9 | Article 1173 Boloix et al. PVT1 in Pediatric Cancer FIGURE 3 | Kaplan-Meier survival curves based on PVT1 expression in different pediatric tumors. Kaplan-Meier plots were generated using the “R2: Genomics Analysis and Visualization Platform” software. Patient samples were split according to high (above median) or low (below median) PVT1 expression levels from the following datasets: Wilm’s tumor (n = 148, R2 ID:ps_avgpres_wilmsocga148_u133a), neuroblastoma (n = 476, GSE45547), mantle cell lymphoma (n = 122, GSE93291), Ewing’s sarcoma (n = 52, GSE17679), osteosarcoma (n = 88, GSE42352), and pediatric glioma (n = 47, SE19578). PTV1 as a potential biomarker. CircRNA are uncapped RNA PVT1 as a ceRNA in Pediatric Tumors molecules characterized by a covalently closed loop structure The most common oncogenic attribute of lncRNA is their without a 3′ polyadenylated tail (111). Kun-Peng et al. found capacity to sequester tumor-suppressive miRNA. Some examples circPVT1 to be upregulated in OS tumors compared with of PVT1 have already been described in adult and pediatric normal tissues. Moreover, higher circPVT1 levels were found malignancies (Table 1). For example, Song et al. showed that in chemoresistant tumors and, furthermore, high levels of PVT1 acts as a sponge to repress miR-497-5p in osteosarcoma circPVT1 were associated with poor overall survival. Finally, cells. In fact, silencing PVT1 resulted in upregulation of miR- those authors demonstrated that the expression of circPVT1 497-5p levels which, in turn, target hexokinase 2 (HK2), in serum had better sensitivity and specificity than currently- a key metabolic enzyme that regulates glucose metabolism. used OS markers such as alkaline phosphatase (112). Concurring Conversely, overexpression of PVT1 reduced miR-497-5p levels with these observations, high levels of circPVT1 (but not total and HK2 was upregulated, thereby contributing to enhanced PVT1) were found to be overexpressed in acute lymphoblastic glycolysis, proliferation and motility (97). Similar observations leukemia (ALL) compared to normal bone marrow samples were reported for the interaction of miR-195-5p and PVT1 also in (113); however, their potential to predict patient outcome osteosarcoma. In that case, the authors demonstrated that PVT1 remains to be determined. silencing resulted in increased migration, invasion potential and Frontiers in Oncology | www.frontiersin.org 6 November 2019 | Volume 9 | Article 1173 Boloix et al. PVT1 in Pediatric Cancer cell survival, effects that were partially mediated by miR-195- CONCLUSIONS AND FUTURE 5p (95). Interestingly, miR-195-5p and miR-497-5p are in the PERSPECTIVES same cluster and belong to the same family, i.e., are potentially regulators of the same biological processes. Several indicators suggest that PVT1 could be a future Finally, a recent study identified PVT1 as an important prognostic and therapeutic target for some pediatric tumors. contributor to resistance to gemcitabine, a nucleoside analog First of all, PVT1 is a necessary element for the correct currently used for the treatment of osteosarcoma. Sun et al. embryonic development and differentiation of certain cellular showed that PVT1 interacts and inhibits the function of miR- lineages. Aberrant PVT1 expression may account for the 152-3p, thereby promoting increased resistance to gemcitabine “undifferentiated” state observed in almost all pediatric by enhancing the activation of C-MET/PI3K/AKT pathway (96). malignancies. Second, the mutational burden of pediatric tumors These first examples are just the tip of the iceberg, since PVT1 is ∼14 times lower than adult tumors (118), which suggests can potentially bind to many more miRNA and should therefore that epigenetic alterations are more likely to participate in be considered in future studies. Indeed, mining the data available tumorigenesis or tumor progression than in adult tumors. at the experimentally-validated miRNA-LnRNA interactions of Third, the fact that PVT1 has the capacity to bind and modulate the LncBASE (114), revealed that more than 30 different miRNAs the function of multiple tumor-suppressive miRNA, places are able to interact with PVT1. PVT1 as a master regulator of several biological processes regulated by these miRNA. Further safety studies analyzing Potential Use of PVT1 as a Therapeutic the impact of a systemic PVT1 loss of function and finding Target in Pediatric Cancer an appropriate clinical formulation to administer small RNA RNA-based therapies are an emerging alternative to conventional molecules targeting PVT1, are the next steps in implementing treatments owing, in part, to their potential to target all the use of PVT1-based therapies for the treatment of tumors of the transcriptome, thereby expanding the number of potential childhood and adolescence. targets. Indeed, proof of concept experiments which silence PVT1, such as those mentioned previously [i.e., osteosarcoma AUTHOR CONTRIBUTIONS (97) and ALL (113)] have already shown that targeting PVT1 yielded an anti-tumoral response. RNA interference (RNAi), AB, MM, and RA revised bibliography. CJ designed and created antisense oligonucleotides (ASO) and genome editing (i.e., the figures. AS, JR, JS, and SG provided intellectual support and CRISPR/Cas9 system) are the only currently-available tools to expertise in the field of pediatric cancer. AB, MM, and MS wrote silence lncRNAs [reviewed in (115, 116)]. Furthermore, the the original manuscript. All authors contributed to the edition function of PVT1 that needs to be targeted will depend on its and the critical review of the manuscript. subcellular distribution. For example, cytosolic PVT1 could be sensitive to siRNA or shRNA-based strategies, whereas nuclear FUNDING PVT1 would be more sensitive to ASO. One of the examples in which targeting PVT1 could be a new therapeutic strategy The funding was received by Ministerio de Educación, Cultura y was reported recently. Wu et al. showed that siRNA-mediated Deporte (Grant no. FPU16/01099), Instituto de Salud Carlos III silencing of PVT1 caused a marked reduction in cell viability (Grant no. CP16/00006), Instituto de Salud Carlos III (Grant no. in retinoblastoma cell lines. Furthermore, shRNA-mediated loss PI17/00564), and Asociación Española Contra el Cáncer (Grant of PVT1 function also resulted in a reduced tumor growth no. LABAE18009SEGU). in vivo (105). In addition to, or instead of, targeting the whole PVT1 ACKNOWLEDGMENTS molecule, targeting single components of PVT1 may be necessary. For example, in a tumor context where the miRNA The authors thank Ms. Christine O’Hara for English language encoded within PVT1 participate in disease progression, the correction and the members of the Group of Translational use of anti-miR would be recommended. Alternatively, if the Research in Child and Adolescent Cancer for helpful suggestions oncogenic function of PVT1 is related to its capacity to bind and and discussion. 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Long non-coding RNA PVT1 terms of the Creative Commons Attribution License (CC BY). The use, distribution enhances the viability and invasion of papillary thyroid carcinoma cells by or reproduction in other forums is permitted, provided the original author(s) and functioning as ceRNA of microRNA-30a through mediating expression of the copyright owner(s) are credited and that the original publication in this journal insulin like growth factor 1 receptor. Biomed Pharmacother. (2018) 104:686– is cited, in accordance with accepted academic practice. No use, distribution or 98. doi: 10.1016/j.biopha.2018.05.078 reproduction is permitted which does not comply with these terms. Frontiers in Oncology | www.frontiersin.org 10 November 2019 | Volume 9 | Article 1173