Cancer and Metastasis Reviews (2019) 38:783–811 https://doi.org/10.1007/s10555-019-09829-x MicroRNA dysregulation interplay with childhood abdominal tumors Karina Bezerra Salomão1 & Julia Alejandra Pezuk2 & Graziella Ribeiro de Souza1 & Pablo Chagas1 & Tiago Campos Pereira3 & Elvis Terci Valera1 & María Sol Brassesco3 Published online: 17 December 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that differentiate them from adult cancers. Current molecular approaches have greatly improved the understanding of the distinctive pathology of each tumor type and enabled the characterization of novel tumor biomarkers. As seen in abdominal adult tumors, microRNAs (miRNAs) have been increasingly implicated in either the initiation or progression of childhood cancer. Moreover, besides predicting patient prognosis, they represent valuable diagnostic tools that may also assist the surveillance of tumor behavior and treatment response, as well as the identification of the primary metastatic sites. Thus, the present study was undertaken to compile up- to-date information regarding the role of dysregulated miRNAs in the most common histological variants of AT, including neuroblas- toma, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adrenal tumors. Additionally, the clinical implications of dysregulated miRNAs as potential diagnostic tools or indicators of prognosis were evaluated. Keywords miRNA . Neuroblastoma . Nephroblastoma . Hepatoblastoma . Hepatocarcinoma . Adrenal tumors 1 MicroRNA biogenesis and function retaining the hairpin (pre-miRNA, ~ 70 nucleotides long), which is translocated by Exportin-5 to the cytoplasm, and then Fundamentally, all cellular programs are controlled by genes: processed by another endoribonuclease (Dicer) into the growth, senescence, division, metabolism, stemness, mobility, miRNA duplex. Once loaded into the RNA-induced silencing apoptosis, and more. In turn, gene expression is also tightly complex (RISC), one strand of the duplex is destroyed while regulated by different mechanisms, such as microRNAs the other directs RISC to messenger RNAs (mRNAs) with (miRNAs). miRNAs are a class of small, non-protein coding partial (or total) complementary sequences [2]. RISC then RNA molecules (approximately 22 nucleotides long) that me- interrupts the production of the protein by one of the different diate post-transcriptional gene silencing [1]. These short RNA ways: inhibition of translation (which is reversible), regulators are encoded by “miRNA genes,” which are tran- decapping, deadenylation, or cleavage [3]. MiRNAs often, scribed by RNA polymerase II as a primary miRNA (pri- but not exclusively, hybridize with complementary sites with- miRNA) containing a 5′ CAP, a 3′ poly-A tail, and an internal in the 3′ untranslated region (UTR) of targeted mRNAs. One hairpin-structured region. Pri-miRNA is then cleaved by the specific miRNA may target many different mRNAs, and nuclear endoribonuclease Drosha into the precursor miRNA thereby, one mRNA may also be controlled by many distinct miRNAs. The region comprising nucleotides 2 to 8 of the 5′ terminus of miRNAs is known as the “seed” sequence: a re- * María Sol Brassesco gion of total complementarity to the targeted mRNA that is [email protected] critical for miRNA pairing and function [3]. Sixty percent of all genes in the human genome display at 1 Ribeirão Preto Medical School, University of São Paulo, Av. Dr. least one conserved site for miRNA binding [4]. Consequently, Rudge Ramos, 1501 - Jardim Abc, São Bernardo do all biological processes are regulated by this class of molecules Campo, SP 09639-000, Brazil [5–9]. Due to their roles in several key events, dysregulation of 2 Anhanguera University of São Paulo, UNIAN/SP, Av. Dr. Rudge miRNAs has also been associated with diverse aspects of can- Ramos, 1501 - Jardim Abc, São Bernardo do Campo, SP 09639-000, Brazil cer biology [10]. Thus, in this review, we compile growing information on miRNAs’ dysregulation along with a summary 3 Biology Department, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900 of opportunities for their use as specific biomarkers in most - Vila Monte Alegre, Ribeirão Preto, SP 14040-900, Brazil prominent pediatric abdominal tumors. 784 Cancer Metastasis Rev (2019) 38:783–811 2 Abdominal tumors in children Moreover, due to their multi-target nature, miRNAs act si- multaneously on several signaling pathways, affecting process- Abdominal tumors (AT) in the pediatric population, in- es such as metabolism control, cell differentiation, and apopto- cluding renal tumors, sympathetic nervous system tumors, sis [19]. miRNAs that repress tumor suppressor genes and malignant liver tumors, and gonadal tumors, correspond thereby favor tumor growth are called oncogenes or to ~ 17% of all pediatric solid tumor cases [11]. oncomiRs and are generally upregulated in tumors. Clinically, these masses vary in their clinical signs and Conversely, miRNAs that negatively regulate the expression symptoms, depending on the causative physiopathology: of genes related to tumor growth are considered tumor suppres- they can be largely asymptomatic and uncovered during sors and are downregulated in tumors. Their downregulation routine clinical exam (as for nephroblastomas) or be ob- may result in mutations in genomic regions associated with served in the context of a systemic disease in a severely ill cancer or in fragile sites of the genome [20], as a result of patient. Many abdominal masses in children can develop epigenetic modifications [21, 22], or through altered function- in utero (i.e., congenital mesoblastic nephroma, teratomas, ing of elements from their biogenesis machinery such as Dicer, neuroblastoma, and mesenchymal hamartoma of the liver, Drosha, DGCR8, Argonaut, and Exportin-5 [23]. In this re- amongothers).Inthislifeperiod, other non-neoplastic or spect, the most striking evidence that malfunction of a pivotal benign conditions need to be ruled out with differential enzyme involved in miRNA processing has direct implications diagnosis. These conditions encompass abdominal cystic in tumor development in children is portrayed by the DICER1 lymphangiomas [12], benign liver lesions (infantile hepat- genetic syndrome, an autosomal dominant inherited condition ic hemangioendothelioma, mesenchymal hamartoma of that leads to abnormal endonuclease activity [24–26]. the liver, nodular regenerative hyperplasia, and focal nod- Described abdominal masses on DICER1-mutated children in- ular hyperplasia [13]), and congenital hydronephrosis clude cystic nephroma, Wilms tumor, and ovary cancer (partic- [14]. Among the most common ATs in children are ularly Sertoli-Leydig cell tumors) [26]. nephroblastoma (Wilms tumor), neuroblastoma, In the following sections, we present up-to-date informa- hepatoblastoma, germ-cell tumors, and rhabdomyosarco- tion about the altered miRNAs and their interplay with most ma [11]. Contrary to what is observed for the adult pop- common abdominal cancers in children: neuroblastoma, ulation, ATs in children exhibit embryonal histologies, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adre- with direct implications on the neoplastic cell-of-origin, nal tumors. mechanisms related to tumorigenesis, and the therapeutic response of these lesions. 2.1 Neuroblastoma The evaluation of a child with an abdominal mass involves a number of diagnostic considerations on physical examina- Neuroblastoma (NB) is one of the most common solid tumors tion, including age and sex of the patient, the location of the in children. It originates from precursor cells of the parasym- mass, and the presence/absence of other related signs and pathetic nervous system and accounts for 15% of cancer- symptoms [15]. Diagnostic imaging (through magnetic reso- related deaths during childhood. NBs have a heterogeneous nance imaging, computed tomography, and/or ultrasound clinical presentation and course, ranging from spontaneous techniques) and the determination of the organ or tissue of regression to evolution into aggressive phenotypes and subse- origin can provide sufficient information for a diagnosis. quent death. Chromosomal alterations are common in this Most importantly, molecular approaches have greatly im- pathology, including loss of 3p, 11q, and 14q and gain of proved the understanding of the distinctive pathology of each 17q. Non-favorable forms of NB characteristically exhibit am- tumor type and the characterization of novel biomarkers, plification of MYCN (MNA) and are associated with the loss thereby creating new opportunities for therapy refinement to of 1p and gain of 17p [27, 28]. maximize cure and reduce therapy-associated toxicities. MiRNA dysregulation plays an important role in the etiol- In this regard, miRNAs have emerged as valuable tools for ogy of NB (Table 1). The first miRNA described as dysregu- early cancer detection and follow-up. These short non-coding lated in this tumor was miR-34a located at 1p36.23 [29–31]. RNAs have many clinical and therapeutic implications, main- In vitro reintroduction of miR-34a reduced cell proliferation ly due to their stability and specificity which enables their use and induced apoptosis with cell cycle arrest in cell lines car- as diagnostic markers, for surveillance of tumor progression rying a 1p36