Identification and network analysis of candidate microRNA biomarkers in neuroblastoma : A meta-analysis

Neuroblastoma constitutes roughly 8% of all childhood cancers where 95% of all neuroblastoma cases occur before the age of 10. The survival rate of infants and young children is very poor, which alone contributes to research novel biomarkers for classification methods, improved diagnosis and better anti-tumor therapies. The aim of this meta-analysis was to identify dysregulated miRNAs in neuroblastoma that has the potential to be used as antioncogenic biomarkers for diagnostic interventions. Additionally, explore miRNA interconnectedness on a systemic level and conversely extend the support of using miRNAs as biomarkers. A comprehensive literature search was performed within NIH-PubMed, NCBI-PMC and in the reference list of already reviewed publications, which yielded 9 eligible publications. Quality of evidence was assessed according to the guidelines adapted from MIAME, MINSEQE and MIQE. miRNet 2.0 was used to find the most significantly enriched annotations linked to neuroblastoma. A total of 251 samples (Cancer: 141; Control: 110) was reported by the 9 studies. These involved 66 dysregulated miRNAs (Up-regulated: 43; Down-regulated: 23) which was used for enrichment analysis. Four miRNAs (miR-17-5p, -92a-3p -421, -125b) were significantly linked to neuroblastoma, and associated secondary diseases; medulloblastoma (-92a-3p, -125b), bladder cancer (-17-5p, -125b), acute myeloid leukemia (-92a-3p, -125b) and cardiac hypertrophy (- 125b). miR-125b showed exceptional interconnectivity with these diseases and a multidimensional potential in neural tumorigenesis. This study showed that dysregulation and biological processes of these miRNAs were concurrent with the original studies, endorsing that these miRNAs have potential as diagnostic indicators or classifiers of such diseases.Popular scientific summary Neuroblastoma (NB) is one of the most common types of pediatric neurological cancers in children and constitutes roughly 8% of all childhood cancer types, in which 95% of all NB cases occur before the age of 10. Even with frequent advancements in medical diagnosis and anti-tumor therapies, the current treatment options for patients with NB offers a survival rate that is very poor. This alone is a reason to pursue developing novel classification methods, improve diagnosis and research better anti-tumor therapies. Micro Ribonucleic Acids (miRNAs) are small non-coding single stranded biomolecules that have gotten a lot of attention in recent years due to their ability to regulate genes involved in various biological cancer processes, such as; tumor growth and development. miRNAs regulate these processes by altering the function of messenger RNAs (mRNAs), which are single-stranded biomolecules that resembles a piece of genetic code from the DNA of an organism cell. When these mRNAs become dysregulated, their cancer-promoting genes are disrupted which prevent them from working properly, leading to tumor regression or termination. The effect of this biological event is then objectively measured by using the miRNA as an indicator, also known as a biomarker. miRNA biomarkers have massive potential to improve various medical applications, such as; faster and more accurate diagnosis, detailed disease-classification and more precise drug trial predictions. However, a lot of individual studies have been published about the same miRNAs, which report a variation of conclusions. This makes it more difficult to determine the true nature of miRNAs. This issue can be addressed with systematic reviews and meta-analyses, which could yield additional support and give a broader picture of how miRNAs regulate different biological processes in NB. A meta-analysis is a scientific statistical process that combines the results of many research publications associated with the same scientific question and presents the best collective estimate of truth with increased precision than what could be achieved from individual studies alone. Thus, meta-analysis is an important tool in research which makes sure that the most trustworthy effect estimate can be achieved among many similar answers. The aim of this meta-analysis was to identify dysregulated miRNAs in NB that has the potential to be used as anti-cancer promoting biomarkers for diagnostic interventions. Additionally, explore how different miRNAs are connected to NB and conversely extend the support of using miRNAs as biomarkers. The end goal of this meta-analysis is to provide more reliable evidence for further research that can improve the life expectancy of NB patients in the future. In this study, 4 miRNAs (miR-17-5p, -92a-3p -421 and -125b) were identified to be significantly linked to NB, and associated secondary diseases; medulloblastoma (-92a-3p & -125b), bladder cancer (-17-5p & -125b), acute myeloid leukemia (-92a-3p & -125b) and cardiac hypertrophy (- 125b). Specifically, miR-125b showed exceptional interconnectivity for these diseases and potential to indirectly down-regulate n-Myc in NB, a gene that promote cancer cell proliferation. miR-125b was also found to be a significant sole regulator and effector of the CDX2 gene responsible for cancer cell differentiation in acute myeloid leukemia, a relationship that has been supported by other publications. This meta-analysis showed that the reported dysregulation and biological processes of these miRNAs were concurrent with the original studies, endorsing that these miRNAs have potential as diagnostic indicators or classifiers of such diseases while warranting that the gene regulatory function of miRNAs are becoming more intricate than previously thought