Novel micro RNA-based therapies for the treatment of neuroblastoma

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Segura" "autores" => array:7 [ 0 => array:3 [ "nombre" => "Ariadna" "apellidos" => "Boloix" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Laia" "apellidos" => "París-Coderch" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Aroa" "apellidos" => "Soriano" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Josep" "apellidos" => "Roma" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Soledad" "apellidos" => "Gallego" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 5 => array:3 [ "nombre" => "Josep" "apellidos" => "Sánchez de Toledo" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 6 => array:4 [ "nombre" => "Miguel F." "apellidos" => "Segura" "email" => array:2 [ 0 => "miguel.segura@vhir.org" 1 => "miguelsegu@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Grupo de Investigación Traslacional en el Cáncer de la Infancia y Adolescencia, Institut de Recerca, Vall d’Hebron, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Oncología y Hematología Pediátricas, Hospital Universitario Vall d’Hebron, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuevas estrategias terapéuticas para el neuroblastoma basadas en el uso de microRNAs" ] ] "textoCompleto" => "IntroductionNeuroblastoma (NB) is a tumour of the sympathetic nervous system. It is considered an embryonal cancer and most cases occur in children and adolescents. It is estimated that about 15,000 new cases of paediatric cancers are diagnosed yearly in Europe, with approximately 8–10% corresponding to neuroblastomas, the incidence of which is 1.8 cases per million. Neuroblastoma accounts for 15% of all cancer-related deaths in children, and is the embryonal tumour with the lowest 5-year relative survival.<a class="elsevierStyleCrossRef" href="#bib0205">1</a> The primary site is often one of the adrenal glands, but it may also originate in nervous tissues of the cervical region, thorax, abdomen and pelvis. Patients with NB are assigned to different risk groups based on their clinical and pathological characteristics, such as stage of disease (INSS), age at diagnosis, MYCN oncogene amplification, tumour histology (Shimada classification) and DNA ploidy.While the survival of low- and intermediate-risk patients is excellent, high-risk patients have a poor prognosis and require intensive chemotherapy regimens. In spite of the intensive regimens, more than 60% of children with NB are not cured.<a class="elsevierStyleCrossRefs" href="#bib0210">2,3</a>Treatment of high-risk neuroblastomaThe treatment sequence applied to high-risk neuroblastoma involves four phases: induction therapy, local control, consolidation, and treatment of residual disease with biologic therapy.<a class="elsevierStyleCrossRef" href="#bib0220">4</a> The induction regimen consists of a combination of anthracyclines, alkylators, platinum compounds and topoisomerase II inhibitors known as COJEC (cisplatin, vincristine, carboplatin, etoposide and cyclophosphamide). It is usually administered in eight cycles at 10-day intervals. The aim of this period of intensive chemotherapy is to reduce the size of the primary tumour (local control) to facilitate its surgical resection.<a class="elsevierStyleCrossRef" href="#bib0225">5</a> After surgery, treatment enters the consolidation phase with dose-intensive myeloablative chemotherapy (busulfan, melphalan), followed by autologous hematopoietic stem cell transplantation. When the patient has recovered, local radiotherapy is administered at the primary tumour site and metastatic foci.Last of all, biologic agents are used to treat residual disease, such as antibodies against specific NB antigens (such as anti-GD2) and 13-cis-retinoic acid as a differentiating agent, alone or combined with IL-2, which helps activate the immune system.Drug resistanceDespite sequential and combined treatments, 60% of the patients experience recurrence and develop metastases.<a class="elsevierStyleCrossRefs" href="#bib0210">2,5</a> The progression of high-risk NB is associated to development of drug resistance, usually to multiple drugs (multidrug resistance [MDR]). Multidrug resistance is usually due to various cellular factors and cell signalling pathways, and is one of the major barriers to successful chemotherapy. Some elements that are typical of high-risk NB contribute to MDR, such as increased oncogene expression (for instance, of MYCN), increased signalling by tyrosine kinase receptors (BDNF-TrkB) or altered function in tumour suppressor genes (such as p53).<a class="elsevierStyleCrossRefs" href="#bib0230">6–9</a> There is also evidence of altered expression or activation patterns of crucial elements in apoptosis signalling pathways.<a class="elsevierStyleCrossRefs" href="#bib0250">10,11</a> Furthermore, acquired resistance to chemotherapy may be caused by increased drug excretion from cells due to overexpression of membrane transporters, such as those in the ABC family.<a class="elsevierStyleCrossRefs" href="#bib0260">12,13</a>Given the multiple mechanisms that can lead to resistance to conventional therapies in NB, it is unlikely that treatments addressing a single target will suffice to treat tumours successfully. Therefore, we should strive to identify molecules capable of affecting multiple cell processes to improve response to treatment.Epigenetic therapies as a new alternativeThe field of epigenetics comprehends various mechanisms of gene expression that involve the structural modification of chromatin (for instance, DNA methylation or histone acetylation) and post-transcriptional regulation by noncoding RNAs (such as microRNAs). Changes in epigenetic patterns have been observed in NB tumour cells, including alterations in histone acetylation or aberrant methylation of promoter regions of DNA in specific genes such as caspase-8<a class="elsevierStyleCrossRef" href="#bib0270">14</a> or in large-scale blocks in chromosomes.<a class="elsevierStyleCrossRef" href="#bib0275">15</a> These changes are directly related with patient survival,<a class="elsevierStyleCrossRef" href="#bib0280">16</a> tumour metastatic potential<a class="elsevierStyleCrossRef" href="#bib0285">17</a> and drug resistance.<a class="elsevierStyleCrossRef" href="#bib0290">18</a>Thus, epigenetic therapies are emerging as an alternative to conventional treatment and aim to reverse epigenetic changes that may be contributing to the aggressiveness of tumours. Histone deacetylase inhibitors (for instance, valproic acid) are an example of the “epigenetic drugs” that are being researched; they are currently undergoing clinical trials and have shown beneficial effects in patients with minimal side effects.<a class="elsevierStyleCrossRef" href="#bib0295">19</a>Parallel to the study of drugs that modulate chromatin structure or function, there is growing interest in the therapeutic use of post-transcriptional regulators such as noncoding RNAs. The most promising candidates are microRNAs (miRNAs), small noncoding RNAs (18–25 nucleotides) that regulate gene expression through direct interaction with the 3′UTR region of target molecules, inhibiting their translation or promoting their degradation.MicroRNA genesis and functionMicroRNA genes can be located in intergenic regions, in introns (also known as mirtrons) or in exons of coding or noncoding genes. They can be transcribed by RNA polymerase II–III into simple units from their own promoter, or into more complex molecules containing two or more miRNAs (known as clusters) from a common promoter. The primary transcript (known as pri-miRNA) contains a cap structure at the 5′ end and a poly(A) tail at the 3′ end. This molecule folds into a hairpin structure that is recognised by the Drosha and DGCR8 enzymes, which cleave the ends of the hairpin generating a shorter precursor (∼70–80 nucleotides) called pre-miRNA. This pre-miRNA is exported to the cytoplasm by the action of the XPO5 enzyme and processed by the DICER1 endonuclease, giving rise to the functional double-stranded molecule (18–25 nucleotides). Finally, the two strands are separated and incorporated to the RNA-induced signalling complex (RISC), a multiprotein complex whose function is to bring miRNAs to their target mRNA. Both strands (5p and 3p) may be functionally relevant, independently of their abundance and stability.Generally, the mature form of the miRNA binds the 3′UTR region of its target molecules by means of a sequence of 7 or 8 nucleotides at the 5′ end of the miRNA known as the seed sequence that is highly complementary to the 3′UTR sequence of the target. Once the RISC–miRNA is positioned on the target, inhibition of translation and/or degradation of the mRNA take place. In very specific cases, miRNAs may exert their regulatory function on expression by binding the 5′UTR region.<a class="elsevierStyleCrossRef" href="#bib0300">20</a>Use of microRNAs as a clinical toolThere is a growing number of preclinical trials of miRNA-based therapies that have demonstrated improved, additive or similar effects to conventional treatments. Their use may offer a number of technical advantages:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.MicroRNAs are regulatory elements that may affect multiple mRNAs simultaneously, therefore affecting different components of a single molecular signalling pathway or even different pathways. This minimises the possibility of compensation by redundant pathways or different proteins of the same family.</li><li class="elsevierStyleListItem" id="lsti0010">2.Unlike mRNAs, mature miRNAs are already functional gene products and do not require additional transcriptional regulation to carry out their functions.</li><li class="elsevierStyleListItem" id="lsti0015">3.Lastly, miRNAs are stable in frozen tissues and in formalin-fixed and paraffin-embedded (FFPE) tissue samples. This allows their extraction from clinical biopsies and their quantification by standardised methods such as quantitative PCR at any point during a patient's treatment.</li></ul>MicroRNAs and neuroblastomaLin et al. were the first researchers that observed that the expression profile of a subset of miRNAs could be used to classify high- and low-risk patients with a high sensitivity and specificity.<a class="elsevierStyleCrossRef" href="#bib0305">21</a> To date, numerous miRNAs have been identified that regulate different oncogenic properties in NBs. In this section, we will highlight the miRNAs that have shown therapeutic effects in preclinical models (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>MicroRNAs that function as tumour suppressorsThe first miRNA considered to be a suppressor of NB was miR-34a.<a class="elsevierStyleCrossRef" href="#bib0310">22</a> This miRNA is located in chromosomal region 1p36 (which is frequently deleted in NB) and regulated by the tumour suppressor gene TP53.<a class="elsevierStyleCrossRef" href="#bib0315">23</a> Therefore, the therapeutic strategy is aimed at restoring the levels of this miRNA. In fact, its overexpression results in decreased cell proliferation and increased cell death by apoptosis, both in vitro and in vivo.<a class="elsevierStyleCrossRef" href="#bib0320">24</a>One of the first strategies used to identify miRNAs with therapeutic potential was analysing the expression of different miRNAs and its correlation with different parameters of tumour aggressiveness. This approach led to the identification of miR-542, which seems to be one of the miRNAs with the lowest levels of expression in NB and is highly associated with poor patient survival. The overexpression of miR-542-5p in orthotopic models of NB caused a clear reduction in tumour volume.<a class="elsevierStyleCrossRef" href="#bib0325">25</a> In a recent study on mice with NB xenotransplants, treatment with nanoparticles loaded with miR-542-3p resulted in decreased proliferation and increased cell death by apoptosis in the tumours.<a class="elsevierStyleCrossRef" href="#bib0330">26</a>Another approach has been to study miRNAs that may play a role in the modulation of genes or processes known to be involved in NB. The first obvious focus of investigation was miRNA regulation of MYCN. The results of this research allowed the identification of a set of miRNAs that could suppress expression of the MYCN protein, including miR-34a/c, miR-449, miR-19ab, miR-101 and let-7/miR-202.<a class="elsevierStyleCrossRef" href="#bib0335">27</a> However, there is only evidence in support of the therapeutic potential of let-7. Molenaar et al. elegantly demonstrated that LIN28B, a regulator of the processing of let-7, is amplified in high-risk NB and is therefore partly responsible for the low expression of let-7 and the ensuing overexpression of MYCN.<a class="elsevierStyleCrossRef" href="#bib0340">28</a>The transcription factor PPARγ is also overexpressed in NB, which is partly due to the loss of expression of miRNAs such as miR-27b. The expression levels of miR-27b are low in NB, and treatment of mice with intraperitoneal injections of this miRNA resulted in a significant reduction of tumour growth.<a class="elsevierStyleCrossRef" href="#bib0345">29</a> Treatment with miR-200a of mice with NB cell line xenotransplants achieved similar results. This miRNA belongs to the miR-200 family, the expression of which has been found to be altered in multiple tumours.<a class="elsevierStyleCrossRef" href="#bib0350">30</a> The therapeutic effects of the increased expression of miR-200a have been attributed to inhibition of the expression of the transcription factor AP2-γ.<a class="elsevierStyleCrossRef" href="#bib0355">31</a>Several studies have demonstrated that treatment with miRNAs may contribute to limiting the metastatic potential of NB cells. We find an early example of this in the work of Zhang et al., who analysed the regulation of the MMP-14 metalloproteinase by miRNAs. MMP-14 is a protein involved in migration, invasion and metastasis, so it can be a therapeutic target in NB. The authors demonstrated that overexpression of miR-9 can reduce the levels of MMP-14, leading to a reduction in tumour growth and metastasis of NB cells.<a class="elsevierStyleCrossRef" href="#bib0360">32</a> The expression of MMP-14 is directly regulated by hypoxia-inducible factor 2 alpha (HIF-2α). Recent evidence shows that this factor can also be expressed in non-hypoxic tumour regions. In turn, this factor may be regulated epigenetically by miR-145. Overexpression of miR-145 in NB xenotransplants caused a reduction in the growth, angiogenesis and metastasis of NB cells.<a class="elsevierStyleCrossRef" href="#bib0365">33</a>Another miRNA involved in metastasis is miR-335. The expression of this miRNA is directly suppressed by oncogene MYCN. This can lead to increased expression of several elements in the TGFβ signalling pathway (such as ROCK, MAPK1 and LRGR1), increasing the metastatic potential of NB cells. An unrelated study identified miR-335 and miR-363 as genes regulated by the gastrin-releasing peptide receptor (GRP-R) protein, involved in the tumorigenesis and metastasis of NB. The overexpression of miR-335 and miR-363 in NB cell lines reduced tumorigenesis and metastasis in vivo.<a class="elsevierStyleCrossRef" href="#bib0370">34</a> It has also been observed that MYCN can cooperate with HDAC2 to repress expression of miRNA, specifically miR-183. Overexpression of miR-183 also sufficed to reduce tumour growth in vivo.<a class="elsevierStyleCrossRef" href="#bib0375">35</a>In some instances, recovering the expression of a single miRNA may not be sufficient to achieve a therapeutic effect, but have beneficial effects in combination with conventional or experimental treatments. Such is the case of miR-138, which regulates the expression of the human telomerase reverse transcriptase (hTERT) gene, responsible for the indefinite growth of tumours. The increased expression of miR-138 achieved by injecting DNA in NB xenografts did not in itself affect tumour growth, but it potentiated the therapeutic effects of flavonoids such as apigenin.<a class="elsevierStyleCrossRef" href="#bib0380">36</a>MicroRNAs that function as oncogenesResearch has identified several miRNAs that are overexpressed in tumours with poor prognosis that may function as oncogenes and whose inhibition may achieve therapeutic effects. One example is the recently described miR-558. This miRNA has an unconventional mechanism of action. Unlike the vast majority of miRNAs, whose main function is to inhibit translation and induce degradation of mRNA, miR-558 binds the promoter region of its target genes, such as the heparanase gene (HSPE), stabilising the mRNA and resulting in higher protein levels. This enzyme is involved in invasive processes, tumour growth and angiogenesis (reviewed in <a class="elsevierStyleCrossRef" href="#bib0385">Ref. 37</a>). On the other hand, Qu et al. demonstrated that intravenous injection of molecules for inhibiting the function of miR-558 (anti-miRs) resulted in decreased HSPE protein levels, which in turn led to decreased tumour growth, angiogenesis and lung metastases.<a class="elsevierStyleCrossRef" href="#bib0390">38</a>One of the main miRNAs whose inhibition has great therapeutic potential is miR-380-5p. This miRNA was identified as a regulator of tumour suppressor gene TP53. While mutations or deletions of this gene are frequent in many tumours, changes in this gene are infrequent in NB.<a class="elsevierStyleCrossRef" href="#bib0395">39</a> Nevertheless, we know that the function of TP53 is essential for the signal transduction of genotoxic stimuli such as those generated by chemotherapy drugs. Thus, one of the mechanisms by which tumour cells can tolerate the expression of the TP53 gene is by post-transcriptional control by means of miRNAs. This seems a plausible mechanism in a specific subset of NB patients. Specifically, high levels of miR-380-5p have been found in patients with MYCN-amplified disease and poor prognoses. Inhibition of miR-380-5p by intraperitoneal injection of anti-miRs has been shown to successfully reduce tumour growth in MYCN-dependent tumours by inducing TP53-mediated cell death.<a class="elsevierStyleCrossRef" href="#bib0400">40</a>Conclusions and future perspectivesThe use of miRNAs in clinical practice is already a reality. In the field of oncology, the first molecule that has entered clinical testing is MRX34. This compound mimics miR-34, a miRNA that functions as a tumour suppressor whose expression is reduced in multiple tumours.One limitation of these compounds is their administration by the intravenous route and devoid of any encapsulation, so that their distribution concentrates mostly in the liver, where they are very effective but are also metabolised and excreted rapidly, limiting their therapeutic effect in less perfused tissues. Therefore, more research is needed to improve the biodistribution of miRNAs, possibly by their encapsulation in nanoparticle vesicles manufactured with biocompatible materials, which result to greater stability and longer circulation in the bloodstream, allowing more time for their accumulation in tumour tissues and thus enhancing their antitumour efficacy.FundingThis study has been funded by the Instituto de Salud Carlos III (CP11/00052, PI14/00561, RD12/0036/0016) and co-funded by the European Regional Development Fund (ERDF), Generalitat de Catalunya (2014-SGR-660) and the Marie Curie Career Integration Grants (n° 618301).Conflict of interestsThe authors have no conflict of interests to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres698453" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec708204" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres698452" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec708205" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Treatment of high-risk neuroblastoma" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Drug resistance" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Epigenetic therapies as a new alternative" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "MicroRNA genesis and function" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Use of microRNAs as a clinical tool" ] 10 => array:3 [ "identificador" => "sec0035" "titulo" => "MicroRNAs and neuroblastoma" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "MicroRNAs that function as tumour suppressors" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "MicroRNAs that function as oncogenes" ] ] ] 11 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusions and future perspectives" ] 12 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 13 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interests" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-06-25" "fechaAceptado" => "2015-07-12" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec708204" "palabras" => array:3 [ 0 => "Neuroblastoma" 1 => "Epigenetics" 2 => "MicroRNA" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec708205" "palabras" => array:3 [ 0 => "Neuroblastoma" 1 => "Epigenética" 2 => "MicroRNA" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Neuroblastoma (NB) is the most common solid tumour in children and adolescents, and accounts for up to 15% of all cancer deaths in this group. It originates in the sympathetic nervous system, and its behaviour can be very aggressive and become resistant to current treatments. A review is presented, summarising the new alternative therapies based on epigenetics, i.e. modulators of gene expression, such as microRNAs and their potential application in the clinical practice of NB treatment." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El neuroblastoma (NB) es el tumor sólido más común en niños y adolescentes y representa hasta un 15% de la muerte infantil asociada al cáncer. Tiene su origen en el sistema nervioso simpático y su comportamiento puede llegar a ser muy agresivo y no responder a los tratamientos actuales. En esta revisión se recogen nuevas alternativas terapéuticas basadas en la epigenética, es decir, en moduladores de la expresión génica como los microRNAs y su potencial aplicación clínica en NB." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Boloix A, París-Coderch L, Soriano A, Roma J, Gallego S, Sánchez de Toledo J, et al. Nuevas estrategias terapéuticas para el neuroblastoma basadas en el uso de microRNAs. An Pediatr (Barc). 2016;85:109.e1–109.e6." ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "NA, not analysed; ↑, increased; ↓, decreased." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MicroRNA \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">↑/↓ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Target genes \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effects of restoration \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">References \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-34a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TIMP2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ proliferation, ↑ apoptosis, ↓ vascularisation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0320">24</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-542-5p \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ proliferation, ↓ metastasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0325">25,26</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Let-7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LIN28B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ growth, ↓ clonability, ↓ cell viability, G1 cell cycle arrest \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0340">28</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-27b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PPARγ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ proliferation, ↓ inflammation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0345">29</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-200a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AP-2γ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ proliferation, ↓ tumour growth \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0355">31</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MMP14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ proliferation, ↓ metastasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0360">32</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-145 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HIF-2α \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ cell and tumour growth, ↓ migration, ↓ invasion and metastasis, ↓ angiogenesis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0365">33</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-335 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SOX4, TNC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ clonability, ↓ metastasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0370">34</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-363 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AMDM15, MYO1B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ clonability, ↓ metastasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0370">34</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-183 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ proliferation, ↑ apoptosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0375">35</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-138 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Proteins involved in apoptosis (Bcl-2, Bax, caspase-3, calpain…) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ clonability, ↑ apoptosis, ↓ cell viability, ↓ tumour growth \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0380">36</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-558 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HPSE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ tumour growth, ↓ invasion, ↓ metastasis, ↓ angiogenesis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0390">38</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">miR-380-5p \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TP53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↓ proliferation, ↑ apoptosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0400">40</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1144670.png" ] ] ] ] "descripcion" => array:1 [ "en" => "MicroRNAs with therapeutic potential in neuroblastoma." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib0205" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Embryonal cancers in Europe" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. 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Novel micro RNA-based therapies for the treatment of neuroblastoma

Nuevas estrategias terapéuticas para el neuroblastoma basadas en el uso de microRNAs

Ariadna Boloixa, Laia París-Codercha, Aroa Sorianoa, Josep Romaa, Soledad Gallegoa,b, Josep Sánchez de Toledoa,b, Miguel F. Seguraa,

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miguel.segura@vhir.org
miguelsegu@gmail.com

Corresponding author.

a Grupo de Investigación Traslacional en el Cáncer de la Infancia y Adolescencia, Institut de Recerca, Vall d’Hebron, Barcelona, Spain

b Servicio de Oncología y Hematología Pediátricas, Hospital Universitario Vall d’Hebron, Barcelona, Spain

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            "etiqueta" => "&#8270;"
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    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Nuevas estrategias terap&#233;uticas para el neuroblastoma basadas en el uso de microRNAs"
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Neuroblastoma &#40;NB&#41; is a tumour of the sympathetic nervous system&#46; It is considered an embryonal cancer and most cases occur in children and adolescents&#46; It is estimated that about 15&#44;000 new cases of paediatric cancers are diagnosed yearly in Europe&#44; with approximately 8&#8211;10&#37; corresponding to neuroblastomas&#44; the incidence of which is 1&#46;8 cases per million&#46; Neuroblastoma accounts for 15&#37; of all cancer-related deaths in children&#44; and is the embryonal tumour with the lowest 5-year relative survival&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">1</span></a> The primary site is often one of the adrenal glands&#44; but it may also originate in nervous tissues of the cervical region&#44; thorax&#44; abdomen and pelvis&#46; Patients with NB are assigned to different risk groups based on their clinical and pathological characteristics&#44; such as stage of disease &#40;INSS&#41;&#44; age at diagnosis&#44; MYCN oncogene amplification&#44; tumour histology &#40;Shimada classification&#41; and DNA ploidy&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">While the survival of low- and intermediate-risk patients is excellent&#44; high-risk patients have a poor prognosis and require intensive chemotherapy regimens&#46; In spite of the intensive regimens&#44; more than 60&#37; of children with NB are not cured&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">2&#44;3</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Treatment of high-risk neuroblastoma</span><p id="par0015" class="elsevierStylePara elsevierViewall">The treatment sequence applied to high-risk neuroblastoma involves four phases&#58; induction therapy&#44; local control&#44; consolidation&#44; and treatment of residual disease with biologic therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a> The induction regimen consists of a combination of anthracyclines&#44; alkylators&#44; platinum compounds and topoisomerase II inhibitors known as COJEC &#40;cisplatin&#44; vincristine&#44; carboplatin&#44; etoposide and cyclophosphamide&#41;&#46; It is usually administered in eight cycles at 10-day intervals&#46; The aim of this period of intensive chemotherapy is to reduce the size of the primary tumour &#40;local control&#41; to facilitate its surgical resection&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a> After surgery&#44; treatment enters the consolidation phase with dose-intensive myeloablative chemotherapy &#40;busulfan&#44; melphalan&#41;&#44; followed by autologous hematopoietic stem cell transplantation&#46; When the patient has recovered&#44; local radiotherapy is administered at the primary tumour site and metastatic foci&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Last of all&#44; biologic agents are used to treat residual disease&#44; such as antibodies against specific NB antigens &#40;such as anti-GD2&#41; and 13-<span class="elsevierStyleItalic">cis</span>-retinoic acid as a differentiating agent&#44; alone or combined with IL-2&#44; which helps activate the immune system&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Drug resistance</span><p id="par0025" class="elsevierStylePara elsevierViewall">Despite sequential and combined treatments&#44; 60&#37; of the patients experience recurrence and develop metastases&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">2&#44;5</span></a> The progression of high-risk NB is associated to development of drug resistance&#44; usually to multiple drugs &#40;multidrug resistance &#91;MDR&#93;&#41;&#46; Multidrug resistance is usually due to various cellular factors and cell signalling pathways&#44; and is one of the major barriers to successful chemotherapy&#46; Some elements that are typical of high-risk NB contribute to MDR&#44; such as increased oncogene expression &#40;for instance&#44; of MYCN&#41;&#44; increased signalling by tyrosine kinase receptors &#40;BDNF-TrkB&#41; or altered function in tumour suppressor genes &#40;such as p53&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">6&#8211;9</span></a> There is also evidence of altered expression or activation patterns of crucial elements in apoptosis signalling pathways&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">10&#44;11</span></a> Furthermore&#44; acquired resistance to chemotherapy may be caused by increased drug excretion from cells due to overexpression of membrane transporters&#44; such as those in the ABC family&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">12&#44;13</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Given the multiple mechanisms that can lead to resistance to conventional therapies in NB&#44; it is unlikely that treatments addressing a single target will suffice to treat tumours successfully&#46; Therefore&#44; we should strive to identify molecules capable of affecting multiple cell processes to improve response to treatment&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Epigenetic therapies as a new alternative</span><p id="par0035" class="elsevierStylePara elsevierViewall">The field of epigenetics comprehends various mechanisms of gene expression that involve the structural modification of chromatin &#40;for instance&#44; DNA methylation or histone acetylation&#41; and post-transcriptional regulation by noncoding RNAs &#40;such as microRNAs&#41;&#46; Changes in epigenetic patterns have been observed in NB tumour cells&#44; including alterations in histone acetylation or aberrant methylation of promoter regions of DNA in specific genes such as caspase-8<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">14</span></a> or in large-scale blocks in chromosomes&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a> These changes are directly related with patient survival&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> tumour metastatic potential<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a> and drug resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">18</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Thus&#44; epigenetic therapies are emerging as an alternative to conventional treatment and aim to reverse epigenetic changes that may be contributing to the aggressiveness of tumours&#46; Histone deacetylase inhibitors &#40;for instance&#44; valproic acid&#41; are an example of the &#8220;epigenetic drugs&#8221; that are being researched&#59; they are currently undergoing clinical trials and have shown beneficial effects in patients with minimal side effects&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">19</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Parallel to the study of drugs that modulate chromatin structure or function&#44; there is growing interest in the therapeutic use of post-transcriptional regulators such as noncoding RNAs&#46; The most promising candidates are microRNAs &#40;miRNAs&#41;&#44; small noncoding RNAs &#40;18&#8211;25 nucleotides&#41; that regulate gene expression through direct interaction with the 3&#8242;UTR region of target molecules&#44; inhibiting their translation or promoting their degradation&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">MicroRNA genesis and function</span><p id="par0050" class="elsevierStylePara elsevierViewall">MicroRNA genes can be located in intergenic regions&#44; in introns &#40;also known as <span class="elsevierStyleItalic">mirtrons</span>&#41; or in exons of coding or noncoding genes&#46; They can be transcribed by RNA polymerase II&#8211;III into simple units from their own promoter&#44; or into more complex molecules containing two or more miRNAs &#40;known as <span class="elsevierStyleItalic">clusters</span>&#41; from a common promoter&#46; The primary transcript &#40;known as <span class="elsevierStyleItalic">pri-miRNA</span>&#41; contains a cap structure at the 5&#8242; end and a poly&#40;A&#41; tail at the 3&#8242; end&#46; This molecule folds into a hairpin structure that is recognised by the Drosha and DGCR8 enzymes&#44; which cleave the ends of the hairpin generating a shorter precursor &#40;&#8764;70&#8211;80 nucleotides&#41; called <span class="elsevierStyleItalic">pre-miRNA</span>&#46; This pre-miRNA is exported to the cytoplasm by the action of the XPO5 enzyme and processed by the DICER1 endonuclease&#44; giving rise to the functional double-stranded molecule &#40;18&#8211;25 nucleotides&#41;&#46; Finally&#44; the two strands are separated and incorporated to the RNA-induced signalling complex &#40;RISC&#41;&#44; a multiprotein complex whose function is to bring miRNAs to their target mRNA&#46; Both strands &#40;5p and 3p&#41; may be functionally relevant&#44; independently of their abundance and stability&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Generally&#44; the mature form of the miRNA binds the 3&#8242;UTR region of its target molecules by means of a sequence of 7 or 8 nucleotides at the 5&#8242; end of the miRNA known as the <span class="elsevierStyleItalic">seed sequence</span> that is highly complementary to the 3&#8242;UTR sequence of the target&#46; Once the RISC&#8211;miRNA is positioned on the target&#44; inhibition of translation and&#47;or degradation of the mRNA take place&#46; In very specific cases&#44; miRNAs may exert their regulatory function on expression by binding the 5&#8242;UTR region&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Use of microRNAs as a clinical tool</span><p id="par0060" class="elsevierStylePara elsevierViewall">There is a growing number of preclinical trials of miRNA-based therapies that have demonstrated improved&#44; additive or similar effects to conventional treatments&#46; Their use may offer a number of technical advantages&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0065" class="elsevierStylePara elsevierViewall">MicroRNAs are regulatory elements that may affect multiple mRNAs simultaneously&#44; therefore affecting different components of a single molecular signalling pathway or even different pathways&#46; This minimises the possibility of compensation by redundant pathways or different proteins of the same family&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Unlike mRNAs&#44; mature miRNAs are already functional gene products and do not require additional transcriptional regulation to carry out their functions&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Lastly&#44; miRNAs are stable in frozen tissues and in formalin-fixed and paraffin-embedded &#40;FFPE&#41; tissue samples&#46; This allows their extraction from clinical biopsies and their quantification by standardised methods such as quantitative PCR at any point during a patient&#39;s treatment&#46;</p></li></ul></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">MicroRNAs and neuroblastoma</span><p id="par0080" class="elsevierStylePara elsevierViewall">Lin et al&#46; were the first researchers that observed that the expression profile of a subset of miRNAs could be used to classify high- and low-risk patients with a high sensitivity and specificity&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">21</span></a> To date&#44; numerous miRNAs have been identified that regulate different oncogenic properties in NBs&#46; In this section&#44; we will highlight the miRNAs that have shown therapeutic effects in preclinical models &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">MicroRNAs that function as tumour suppressors</span><p id="par0085" class="elsevierStylePara elsevierViewall">The first miRNA considered to be a suppressor of NB was miR-34a&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">22</span></a> This miRNA is located in chromosomal region 1p36 &#40;which is frequently deleted in NB&#41; and regulated by the tumour suppressor gene <span class="elsevierStyleItalic">TP53</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a> Therefore&#44; the therapeutic strategy is aimed at restoring the levels of this miRNA&#46; In fact&#44; its overexpression results in decreased cell proliferation and increased cell death by apoptosis&#44; both <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo&#46;</span><a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">One of the first strategies used to identify miRNAs with therapeutic potential was analysing the expression of different miRNAs and its correlation with different parameters of tumour aggressiveness&#46; This approach led to the identification of miR-542&#44; which seems to be one of the miRNAs with the lowest levels of expression in NB and is highly associated with poor patient survival&#46; The overexpression of miR-542-5p in orthotopic models of NB caused a clear reduction in tumour volume&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a> In a recent study on mice with NB xenotransplants&#44; treatment with nanoparticles loaded with miR-542-3p resulted in decreased proliferation and increased cell death by apoptosis in the tumours&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Another approach has been to study miRNAs that may play a role in the modulation of genes or processes known to be involved in NB&#46; The first obvious focus of investigation was miRNA regulation of MYCN&#46; The results of this research allowed the identification of a set of miRNAs that could suppress expression of the MYCN protein&#44; including miR-34a&#47;c&#44; miR-449&#44; miR-19ab&#44; miR-101 and let-7&#47;miR-202&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a> However&#44; there is only evidence in support of the therapeutic potential of let-7&#46; Molenaar et al&#46; elegantly demonstrated that LIN28B&#44; a regulator of the processing of let-7&#44; is amplified in high-risk NB and is therefore partly responsible for the low expression of let-7 and the ensuing overexpression of MYCN&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">28</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The transcription factor PPAR&#947; is also overexpressed in NB&#44; which is partly due to the loss of expression of miRNAs such as miR-27b&#46; The expression levels of miR-27b are low in NB&#44; and treatment of mice with intraperitoneal injections of this miRNA resulted in a significant reduction of tumour growth&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">29</span></a> Treatment with miR-200a of mice with NB cell line xenotransplants achieved similar results&#46; This miRNA belongs to the miR-200 family&#44; the expression of which has been found to be altered in multiple tumours&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">30</span></a> The therapeutic effects of the increased expression of miR-200a have been attributed to inhibition of the expression of the transcription factor AP2-&#947;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Several studies have demonstrated that treatment with miRNAs may contribute to limiting the metastatic potential of NB cells&#46; We find an early example of this in the work of Zhang et al&#46;&#44; who analysed the regulation of the MMP-14 metalloproteinase by miRNAs&#46; MMP-14 is a protein involved in migration&#44; invasion and metastasis&#44; so it can be a therapeutic target in NB&#46; The authors demonstrated that overexpression of miR-9 can reduce the levels of MMP-14&#44; leading to a reduction in tumour growth and metastasis of NB cells&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a> The expression of MMP-14 is directly regulated by hypoxia-inducible factor 2 alpha &#40;HIF-2&#945;&#41;&#46; Recent evidence shows that this factor can also be expressed in non-hypoxic tumour regions&#46; In turn&#44; this factor may be regulated epigenetically by miR-145&#46; Overexpression of miR-145 in NB xenotransplants caused a reduction in the growth&#44; angiogenesis and metastasis of NB cells&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Another miRNA involved in metastasis is miR-335&#46; The expression of this miRNA is directly suppressed by oncogene MYCN&#46; This can lead to increased expression of several elements in the TGF&#946; signalling pathway &#40;such as ROCK&#44; MAPK1 and LRGR1&#41;&#44; increasing the metastatic potential of NB cells&#46; An unrelated study identified miR-335 and miR-363 as genes regulated by the gastrin-releasing peptide receptor &#40;GRP-R&#41; protein&#44; involved in the tumorigenesis and metastasis of NB&#46; The overexpression of miR-335 and miR-363 in NB cell lines reduced tumorigenesis and metastasis <span class="elsevierStyleItalic">in vivo</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a> It has also been observed that MYCN can cooperate with HDAC2 to repress expression of miRNA&#44; specifically miR-183&#46; Overexpression of miR-183 also sufficed to reduce tumour growth <span class="elsevierStyleItalic">in vivo</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In some instances&#44; recovering the expression of a single miRNA may not be sufficient to achieve a therapeutic effect&#44; but have beneficial effects in combination with conventional or experimental treatments&#46; Such is the case of miR-138&#44; which regulates the expression of the human telomerase reverse transcriptase &#40;hTERT&#41; gene&#44; responsible for the indefinite growth of tumours&#46; The increased expression of miR-138 achieved by injecting DNA in NB xenografts did not in itself affect tumour growth&#44; but it potentiated the therapeutic effects of flavonoids such as apigenin&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">MicroRNAs that function as oncogenes</span><p id="par0120" class="elsevierStylePara elsevierViewall">Research has identified several miRNAs that are overexpressed in tumours with poor prognosis that may function as oncogenes and whose inhibition may achieve therapeutic effects&#46; One example is the recently described miR-558&#46; This miRNA has an unconventional mechanism of action&#46; Unlike the vast majority of miRNAs&#44; whose main function is to inhibit translation and induce degradation of mRNA&#44; miR-558 binds the promoter region of its target genes&#44; such as the heparanase gene &#40;HSPE&#41;&#44; stabilising the mRNA and resulting in higher protein levels&#46; This enzyme is involved in invasive processes&#44; tumour growth and angiogenesis &#40;reviewed in <a class="elsevierStyleCrossRef" href="#bib0385">Ref&#46; 37</a>&#41;&#46; On the other hand&#44; Qu et al&#46; demonstrated that intravenous injection of molecules for inhibiting the function of miR-558 &#40;anti-miRs&#41; resulted in decreased HSPE protein levels&#44; which in turn led to decreased tumour growth&#44; angiogenesis and lung metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">One of the main miRNAs whose inhibition has great therapeutic potential is miR-380-5p&#46; This miRNA was identified as a regulator of tumour suppressor gene <span class="elsevierStyleItalic">TP53</span>&#46; While mutations or deletions of this gene are frequent in many tumours&#44; changes in this gene are infrequent in NB&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">39</span></a> Nevertheless&#44; we know that the function of TP53 is essential for the signal transduction of genotoxic stimuli such as those generated by chemotherapy drugs&#46; Thus&#44; one of the mechanisms by which tumour cells can tolerate the expression of the <span class="elsevierStyleItalic">TP53</span> gene is by post-transcriptional control by means of miRNAs&#46; This seems a plausible mechanism in a specific subset of NB patients&#46; Specifically&#44; high levels of miR-380-5p have been found in patients with MYCN-amplified disease and poor prognoses&#46; Inhibition of miR-380-5p by intraperitoneal injection of anti-miRs has been shown to successfully reduce tumour growth in MYCN-dependent tumours by inducing TP53-mediated cell death&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclusions and future perspectives</span><p id="par0130" class="elsevierStylePara elsevierViewall">The use of miRNAs in clinical practice is already a reality&#46; In the field of oncology&#44; the first molecule that has entered clinical testing is MRX34&#46; This compound mimics miR-34&#44; a miRNA that functions as a tumour suppressor whose expression is reduced in multiple tumours&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">One limitation of these compounds is their administration by the intravenous route and devoid of any encapsulation&#44; so that their distribution concentrates mostly in the liver&#44; where they are very effective but are also metabolised and excreted rapidly&#44; limiting their therapeutic effect in less perfused tissues&#46; Therefore&#44; more research is needed to improve the biodistribution of miRNAs&#44; possibly by their encapsulation in nanoparticle vesicles manufactured with biocompatible materials&#44; which result to greater stability and longer circulation in the bloodstream&#44; allowing more time for their accumulation in tumour tissues and thus enhancing their antitumour efficacy&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Funding</span><p id="par0140" class="elsevierStylePara elsevierViewall">This study has been funded by the <span class="elsevierStyleGrantSponsor" id="gs1">Instituto de Salud Carlos III</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs1">CP11&#47;00052</span>&#44; <span class="elsevierStyleGrantNumber" refid="gs1">PI14&#47;00561</span>&#44; <span class="elsevierStyleGrantNumber" refid="gs1">RD12&#47;0036&#47;0016</span>&#41; and co-funded by the <span class="elsevierStyleGrantSponsor" id="gs2">European Regional Development Fund</span> &#40;ERDF&#41;&#44; <span class="elsevierStyleGrantSponsor" id="gs3">Generalitat de Catalunya</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs3">2014-SGR-660</span>&#41; and the <span class="elsevierStyleGrantSponsor" id="gs4">Marie Curie Career Integration Grants</span> &#40;n&#176; <span class="elsevierStyleGrantNumber" refid="gs4">618301</span>&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflict of interests</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Treatment of high-risk neuroblastoma"
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          "titulo" => "Epigenetic therapies as a new alternative"
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          "titulo" => "MicroRNA genesis and function"
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          "titulo" => "Use of microRNAs as a clinical tool"
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          "titulo" => "MicroRNAs and neuroblastoma"
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              "titulo" => "MicroRNAs that function as tumour suppressors"
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              "titulo" => "MicroRNAs that function as oncogenes"
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          "titulo" => "Conclusions and future perspectives"
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    "fechaRecibido" => "2015-06-25"
    "fechaAceptado" => "2015-07-12"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Neuroblastoma &#40;NB&#41; is the most common solid tumour in children and adolescents&#44; and accounts for up to 15&#37; of all cancer deaths in this group&#46; It originates in the sympathetic nervous system&#44; and its behaviour can be very aggressive and become resistant to current treatments&#46; A review is presented&#44; summarising the new alternative therapies based on epigenetics&#44; i&#46;e&#46; modulators of gene expression&#44; such as microRNAs and their potential application in the clinical practice of NB treatment&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El neuroblastoma &#40;NB&#41; es el tumor s&#243;lido m&#225;s com&#250;n en ni&#241;os y adolescentes y representa hasta un 15&#37; de la muerte infantil asociada al c&#225;ncer&#46; Tiene su origen en el sistema nervioso simp&#225;tico y su comportamiento puede llegar a ser muy agresivo y no responder a los tratamientos actuales&#46; En esta revisi&#243;n se recogen nuevas alternativas terap&#233;uticas basadas en la epigen&#233;tica&#44; es decir&#44; en moduladores de la expresi&#243;n g&#233;nica como los microRNAs y su potencial aplicaci&#243;n cl&#237;nica en NB&#46;</p></span>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Boloix A&#44; Par&#237;s-Coderch L&#44; Soriano A&#44; Roma J&#44; Gallego S&#44; S&#225;nchez de Toledo J&#44; et al&#46; Nuevas estrategias terap&#233;uticas para el neuroblastoma basadas en el uso de microRNAs&#46; An Pediatr &#40;Barc&#41;&#46; 2016&#59;85&#58;109&#46;e1&#8211;109&#46;e6&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">NA&#44; not analysed&#59; &#8593;&#44; increased&#59; &#8595;&#44; decreased&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MicroRNA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#8593;&#47;&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Target genes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effects of restoration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">References&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-34a</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TIMP2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; proliferation&#44; &#8593; apoptosis&#44; &#8595; vascularisation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">NA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; proliferation&#44; &#8595; metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#44;26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Let-7</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LIN28B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; growth&#44; &#8595; clonability&#44; &#8595; cell viability&#44; G1 cell cycle arrest&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-27b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PPAR&#947;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; proliferation&#44; &#8595; inflammation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-200a</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AP-2&#947;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; proliferation&#44; &#8595; tumour growth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-9</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MMP14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; proliferation&#44; &#8595; metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-145</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">HIF-2&#945;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; cell and tumour growth&#44; &#8595; migration&#44; &#8595; invasion and metastasis&#44; &#8595; angiogenesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-335</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SOX4&#44; TNC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; clonability&#44; &#8595; metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-363</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AMDM15&#44; MYO1B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; clonability&#44; &#8595; metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-183</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">NA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; proliferation&#44; &#8593; apoptosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-138</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Proteins involved in apoptosis &#40;Bcl-2&#44; Bax&#44; caspase-3&#44; calpain&#8230;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; clonability&#44; &#8593; apoptosis&#44; &#8595; cell viability&#44; &#8595; tumour growth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-558</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">HPSE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; tumour growth&#44; &#8595; invasion&#44; &#8595; metastasis&#44; &#8595; angiogenesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">miR-380-5p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TP53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; proliferation&#44; &#8593; apoptosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">MicroRNAs with therapeutic potential in neuroblastoma&#46;</p>"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Gatta"
                            1 => "A&#46; Ferrari"
                            2 => "C&#46;A&#46; Stiller"
                            3 => "G&#46; Pastore"
                            4 => "G&#46; Bisogno"
                            5 => "A&#46; Trama"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.ejca.2011.12.027"
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                        "tituloSerie" => "Eur J Cancer"
                        "fecha" => "2012"
                        "volumen" => "48"
                        "paginaInicial" => "1425"
                        "paginaFinal" => "1433"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22357215"
                            "web" => "Medline"
                          ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Outcomes of the POG 9340&#47;9341&#47;9342 trials for children with high-risk neuroblastoma&#58; a report from the Children&#39;s Oncology Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46;E&#46; Zage"
                            1 => "M&#46; Kletzel"
                            2 => "K&#46; Murray"
                            3 => "R&#46; Marcus"
                            4 => "R&#46; Castleberry"
                            5 => "Y&#46; Zhang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.21713"
                      "Revista" => array:6 [
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                        "volumen" => "51"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18704922"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
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                ]
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                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;C&#46; Seeger"
                            1 => "C&#46;P&#46; Reynolds"
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                    ]
                  ]
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                    0 => array:1 [
                      "Revista" => array:6 [
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                      "titulo" => "Neuroblastoma&#58; biology&#44; prognosis&#44; and treatment"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;R&#46; Park"
                            1 => "A&#46; Eggert"
                            2 => "H&#46; Caron"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.pcl.2007.10.014"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Clin North Am"
                        "fecha" => "2008"
                        "volumen" => "55"
                        "paginaInicial" => "97"
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                      "titulo" => "High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma&#58; a randomised trial"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46;D&#46; Pearson"
                            1 => "C&#46;R&#46; Pinkerton"
                            2 => "I&#46;J&#46; Lewis"
                            3 => "J&#46; Imeson"
                            4 => "C&#46; Ellershaw"
                            5 => "D&#46; Machin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1470-2045(08)70069-X"
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                        "tituloSerie" => "Lancet Oncol"
                        "fecha" => "2008"
                        "volumen" => "9"
                        "paginaInicial" => "247"
                        "paginaFinal" => "256"
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                          0 => array:2 [
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Article information

ISSN: 23412879
Original language: English

DOI:10.1016/j.anpede.2015.07.032

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Year/Month	Html	Pdf	Total

2024 November	6	8	14
2024 October	50	40	90
2024 September	45	27	72
2024 August	66	58	124
2024 July	37	29	66
2024 June	61	46	107
2024 May	48	28	76
2024 April	59	36	95
2024 March	61	29	90
2024 February	32	31	63
2024 January	46	19	65
2023 December	27	20	47
2023 November	29	19	48
2023 October	29	92	121
2023 September	27	35	62
2023 August	25	27	52
2023 July	30	25	55
2023 June	39	29	68
2023 May	34	29	63
2023 April	26	16	42
2023 March	49	20	69
2023 February	34	22	56
2023 January	23	19	42
2022 December	41	21	62
2022 November	66	32	98
2022 October	62	90	152
2022 September	39	47	86
2022 August	44	61	105
2022 July	25	33	58
2022 June	27	55	82
2022 May	35	29	64
2022 April	26	31	57
2022 March	58	38	96
2022 February	34	23	57
2022 January	51	24	75
2021 December	47	35	82
2021 November	55	40	95
2021 October	70	67	137
2021 September	69	47	116
2021 August	42	36	78
2021 July	66	29	95
2021 June	66	23	89
2021 May	58	44	102
2021 April	84	34	118
2021 March	62	37	99
2021 February	47	16	63
2021 January	66	21	87
2020 December	63	23	86
2020 November	54	24	78
2020 October	58	21	79
2020 September	49	27	76
2020 August	42	7	49
2020 July	57	21	78
2020 June	62	20	82
2020 May	68	12	80
2020 April	35	15	50
2020 March	50	23	73
2020 February	61	15	76
2020 January	55	9	64
2019 December	67	13	80
2019 November	40	10	50
2019 October	46	23	69
2019 September	56	17	73
2019 August	87	20	107
2019 July	48	17	65
2019 June	121	40	161
2019 May	162	12	174
2019 April	77	27	104
2019 March	46	18	64
2019 February	47	19	66
2019 January	47	15	62
2018 December	37	28	65
2018 November	108	34	142
2018 October	157	27	184
2018 September	56	14	70
2018 August	11	0	11
2018 July	16	0	16
2018 June	5	0	5
2018 May	58	0	58
2018 April	22	0	22
2018 March	31	0	31
2018 February	2	0	2
2018 January	15	0	15
2017 December	9	0	9
2017 November	17	0	17
2017 October	14	0	14
2017 September	23	0	23
2017 August	19	0	19
2017 July	26	1	27
2017 June	26	9	35
2017 May	28	12	40
2017 April	19	12	31
2017 March	10	32	42
2017 February	10	8	18
2017 January	4	3	7
2016 December	21	11	32
2016 November	32	17	49
2016 October	16	19	35
2016 September	32	13	45
2016 August	72	11	83
2016 July	16	10	26

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