medulloblastoma is the most common pediatric brain tumor , with an incidence of ~0.5/100,000 children < 15 years old ( 1 ) .
it is classified as grade iv according to the world health organization ( who ) ( 2 ) .
current treatment consisting of surgery , radiotherapy and adjuvant chemotherapy has a limited role in improving the prognosis of patients ( 3,4 ) . novel therapeutic methods based on the specific mechanism of medulloblastoma carcinogenesis
an increasing number of studies have revealed that micrornas ( mirnas / mirs ) serve a role in tumorigenesis ( 59 ) .
gene expression is regulated by thousands of known mirnas , which bind to imperfect complementary sites within the 3 untranslated regions of their target protein - coding mrnas , and repressing the expression of these genes at the level of mrna stability and translation ( 10 ) .
previous research has revealed that mirnas are involved in the regulation of the majority of physiological and pathological process , including development , life span , and metabolism , and their dysregulation contributes to a number of types of disease , notably cancer ( 11 ) .
these small rnas may function as oncogenes or tumor suppressors by modulating the levels of critical proteins , and their relevance in human disease and therapy is currently under investigation ( 12 ) .
an increasing number of studies have demonstrated abnormal mirna expression levels in the central nervous system ( cns ) of cancer patients , suggesting that mirnas may serve as key regulatory components in cancer of the cns ( 5,10,13 ) .
it was observed that 22 mirnas were upregulated and 26 mirnas were downregulated in the tumor tissue .
ingenuity pathway analysis ( ipa ) was used to analyze the regulatory network of the differentially expressed mirna in medulloblastoma .
it was proposed that the pathways exhibited in the network may have an important role in the tumorigenesis of medulloblastoma .
the data were downloaded from the ncbi gene expression omnibus ( geo ) database ( gse42657 , www.ncbi.nlm.nih.gov/geo ) .
the data include 7 control samples ( consisting of 3 cerebellum and 4 frontal lobe controls ) and 9 medulloblastoma samples .
the data from all samples was normalized using the limma package in r software version 3.3.0 ( https://www.r-project.org/ ) .
the selected samples of this profile are exhibited in table i. the differentially expressed genes ( degs ) were obtained with the thresholds of |logfc|>1.0 and p<0.01 , using linear models and empirical bayes methods for assessing differential expression in microarray experiments in the limma package ( table ii ) .
a heat map of the different groups was produced to visualize the degs and cluster the corresponding groups with the differentially expressed mirnas from the tumor tissue , using the r package gplots ( fig .
the dataset ( 48 differentially expressed mirnas ) was uploaded to the ingenuity pathway analysis software version 2016 ( qiagen , inc . ,
valencia , ca , usa ) , using the microrna target filter to find the targeting information .
a total of 40 micrornas targeting 11,757 mrnas were identified by the filter . the core analysis function ( rapid assessment of the signaling and metabolic pathways , molecular networks , and biological processes that are most markedly perturbed in the dataset of interest ) to analyze the associated network functions of the mirnas .
using mirna microarray data from the geo database , 48 mirnas which are differentially expressed in medulloblastoma were identified , compared with the control group ( table ii ) .
the core analysis demonstrated the molecular network interactions and signaling pathways associated with 28 differentially expressed mirnas of medulloblastoma , and their predicted molecular targets were rebuilt using ipa . the network 
organismal injury and abnormalities , reproductive system disease , cancer had an ipa score of 41 , focusing on 17 mirna molecules , and the network  cancer , organismal injury and abnormalities , cell death and survival had an ipa score of 23 , focusing on 11 mirna molecules ( fig .
the most impacted biological processes and diseases regulated by the analyzed mirnas included organismal injury and abnormalities , reproductive system disease and cancer .
the molecular network maps demonstrated that three primary components were identified to be at the central hub of the most significant network with a score of 41 ; these were tumor protein p53 ( tp53 ) , argonaute 2 ( ago2 ) and mitogen activated kinases 3 and 1 ( erk1/2 ) ( fig .
tp53 , sirtuin 1 ( sirt1 ) and y box protein 1 ( ybx1 ) were located in the center of the second network with a core analysis score of 23 ( fig .
the first network included mir-17 - 5p , mir-130a-3p , mir-182 - 5p , mir-18a-5p , mir-19b-3p , mir-4288 , mir-96 - 5p , which were upregulated in the medulloblastoma samples , and mir-128 - 3p , mir-132 - 3p , mir-133a-3p , mir-299a-5p , mir-409 , mir-668 - 3p , which were downregulated . the second notable network ( fig .
2b ) involved upregulated mir-217 - 5p and mir-216a-5p , and downregulated mir-329 , mir-330 and mir-584 , which are associated with the regulation of key regulatory genes in medulloblastoma development , including tp53 , sirt1 and ybx1 .
however , when the cerebellum samples were used as the control , it was observed that 4 mirnas were overexpressed and 5 mirnas were underexpressed in the medulloblastoma ( table iii ) .
the network  cell death and survival , gastrointestinal disease , hepatic system disease had an ipa score of 9 , focusing on 4 mirna molecules ( fig .
mirnas function as master regulators and signal modulators by fine - tuning gene expression in multiple complex pathways .
a number of the mirnas which exhibit dysregulated expression in medulloepithelioma have been reported to serve various roles in carcinogenesis ( 6,7,9 ) . through analysis of a geo mirna expression profiling dataset , mirnas which are over- and underexpressed in medulloblastoma
were identified , including mir-217 , mir-216 , mir-183 , mir-182 and mir-96 , which are upregulated in tumor tissue .
previous research demonstrates that mir-183 - 96 - 182 regulates cell survival , proliferation and migration in medulloblastoma , and increased mir-183 - 96 - 182 expression is associated with aggressive clinical course , high rates of metastasis and poor overall survival ( 8,9,14 ) .
mir-217 and mir-216 were overexpressed in medulloblastoma . however , the role of mir-217 was controversial .
mir-217 is an oncogene that is overexpressed in aggressive human b cell lymphomas ( 15 ) .
however , it may be a tumor suppressor in hepatocellular carcinoma ( 16 ) . in pancreatic intraepithelial neoplasm , pancreatic ductal adenocarcinomas and
further studies are required to determine whether increased expression of mir-217 in medulloblastoma represents an oncogenic effect , or if the dysregulation functions as a potential tumor suppressor . while mir-216 was underexpressed in various types of cancer , including breast cancer , pancreatic cancer and nasopharyngeal carcinoma ( 1921 )
, it may serve as a tumor suppressor to inhibit cell proliferation , invasion and tumor growth .
further studies are required to determine whether increased expression of mir-216 in medulloblastoma represents an oncogenic effect or is a potential tumor suppressor . in the present study ,
marked downregulation of mir-383 , mir-206 , mir-138 , mir-128a / b and mir-133b was identified .
mir-383 , repressing peroxiredoxin 3 at transcriptional and translational levels , suppressed the cell growth of medulloblastoma ( 6 ) .
additionally , mir-206 was downregulated in all the four molecular subgroups of medulloblastoma as well as in cell lines .
orthodenticle homeobox 2 ( otx2 ) , a target gene of mir-206 which is overexpressed in all non - sonic - hedgehog - driven medulloblastomas , is an oncogene in medulloblastoma .
therefore , underexpression of mir-206 contributed to the upregulation of otx2 expression and enhanced growth of medulloblastoma cell lines ( 7 ) .
studies have demonstrated a reduction in the mirnas mir-383 , mir-138 , mir-128a / b , mir-133 , mir-124 and let-7 g in medulloblastoma .
nevertheless , mir-328 , mir-133b , mir-149 , mir-181b and mir-154 were downregulated in the study of ferretti et al ( 5 ) and the present study .
in addition , the present study revealed that mir-433 , mir-488 , mir-584 , mir-329 , mir-299 - 5p , mir-330 , mir-770 - 5p , mir-656 and mir-642 were underexpressed in medulloblastoma , and further research is required to identify whether these mirnas have a specific role in the tumorigenesis of medulloblastoma .
based on microarray analysis , mirnas that distinguish normal brain from medulloblastoma tissue were identified . as presented in the heat map ,
the dysregulated mirnas are more closely associated with the medulloblastoma samples compared with the normal control samples .
additionally , by uploading the mirnas from the first network to the ipa , it was identified that the dysregulated mirnas were associated with key regulatory genes in tumorigenesis , including tp53 , insulin - like growth factor 1 receptor , ago2 and erk1/2 .
the overexpressed mirnas mir-17 - 5p and mir-182 ( log fold change > 2 ) have interactions with tp53 ; studies have demonstrated an association between these mirnas and tp53 in tumorigenesis ( 22,23 ) .
agos are associated with mirnas , due to their function in the rna induced silencing complex ( risc ) , wherein they use small rna guides to recognize targets .
ago2 had an interaction with mirnas that are dysregulated in medulloblastoma , including mir-17 - 5p , mir-128 , mir-96 , mir-433 , mir-383 and mir-138 .
the second network , including mir-217 and mir-216 , which are upregulated in medulloblastoma , exhibits associations with key regulatory genes in medulloblastoma development , including tp53 , sirt1 and ybx1 .
sirt1 is a well understood member of the sirtuin protein class , preventing cell aging and apoptosis of normal cells ( 24,25 ) .
the effects of sirt1 are controversial ; the protein was considered to be a tumor promoter in neuroblastoma , prostate and skin cancer ( 2628 ) , whereas it was considered to be a tumor suppressor in breast and colon cancer ( 29,30 ) .
therefore , sirt1 may serve a role in medulloblastoma and correlate with the formation and prognosis of human medulloblastomas ( 31 ) .
recently , dey et al ( 32 ) proved that ybx1 ( yb1 ) is upregulated across human medulloblastoma subclasses and is required for medulloblastoma cell proliferation .
furthermore , the study identified that the shh : yap : yb1:igf2 axis may be a powerful target for therapeutic intervention in medulloblastoma . when the medulloblastoma samples were compared with the normal cerebellum , 9 dysregulated mirnas were identified .
the 9 mirnas were uploaded to the ipa in order to perform the core analysis .
the network involved 4 downregulated mirnas and was associated with important regulators of tumorigenesis , including met proto - oncogene ( met ) , akt serine - threonine kinase 1 and sterol regulatory element - binding factor 1 ( srebf1 ) .
previous evidence has demonstrated the association between aberrant met signaling and medulloblastoma development ( 33,34 ) .
previous studies have revealed that overexpressed mir-206 may inhibit met in lung cancer ( 35,36 ) , however the function of downregulated mir-206 in medulloblastoma is unknown .
srebf1 is a transcription factor , regulating lipogenesis , which is also involved in tumorigenesis ( 37 ) .
these network components alone are not sufficient to initiate medulloblastoma formation ; the interactions between these dysregulated factors and additional genetic insults promote tumorigenesis . in conclusion , based on the mirna array data in the geo database , mirnas which are differentially expressed in medulloblastoma samples were identified .
certain dysregulated mirnas have been confirmed ; however , further research is required to verify the mirnas which have not been previously identified .
additionally , the ipa core analysis , presenting the interaction of mirnas and counterpart targets , provides a method to understand the tumorigenesis of medulloblastoma .
the results of the present study may provide a potent target for therapeutic intervention or diagnosis in medulloblastomas .
 medulloblastoma is the most common malignant brain tumor of the central nervous system among children . 
 medulloblastoma is an embryonal tumor , of which little is known about the pathogenesis . 
 several efforts have been made to understand the molecular aspects of its tumorigenic pathways ; however , these are poorly understood . 
 microrna ( mirna ) , a type of non - coding short rna , has been proven to be associated with a number of physiological processes and pathological processes of serious diseases , including brain tumors . 
 differentially expressed mirnas serve an important role in numerous types of malignancy . 
 the present study aims to define a differentially expressed set of mirnas in medulloblastoma tumor tissue , compared with normal samples , to improve the understanding of the tumorigenesis . 
 it was identified that 22 mirnas were upregulated and 26 mirnas were downregulated in the tumor tissue compared with the normal group . however , when the medulloblastoma tissue was compared with normal cerebellum tissue , 9 mirnas were identified to be up or downregulated in the tumor samples . 
 the differentially expressed mirnas in the tumor tissue were identified in order to clarify the networks and pathways of tumorigenesis using ingenuity pathway analysis . 
 subsequently , key regulatory genes associated with the development of medulloblastoma were identified , including tumor protein p53 , insulin like growth factor 1 receptor , argonaute 2 , mitogen - activated protein kinases 1 and 3 , sirtuin 1 and y box binding protein 1 . 