ABSTRACT
Recent studies suggest abnormal microRNA (miRNA) expression may have potential prognostic value in childhood acute lymphoblastic leukemia (ALL). In this systematic review, we searched different databases (PubMed, ASH, ASCO, and SIOP) for studies published from 2008 to 2018 that evaluated the prognostic impact of miRNAs in childhood ALL. We also used DIANA-miRPath v3.0 to further characterize the functional role of the significant prognostic miRNAs identified in our systematic review. Here we evaluate 15 studies with a total of 38 different miRNAs and 1545 children with B-cell ALL (B-ALL) or T-cell ALL (T-ALL) recruited over approximately 3 decades (1984-2016) with different treatment protocols and ethnicities. Out of the 15 studies examined, 14 reported 32 dysregulated miRNAs with significant prognostic impact in pediatric ALL patients. Only one Brazilian study reported no significant prognostic effect of 7 miRNAs, while the seventh miRNA (miR-100) showed prognostic significance in a Chinese study. Using DIANA-TarBase v7.0 of DIANA-miRPath v3.0, pathway enrichment analysis revealed 25 miRNAs modulated 24 molecular pathways involved in cancer development. To remove the effect of salvage therapy, 9 studies carried out multivariate cox regression analysis for both relapse-free survival and disease-free survival to develop a panel of 23 miRNAs acting as independent prognostic biomarkers. To enhance the clinical application, utility, and validity of the miRNAs discussed here, their potential prognostic value should be confirmed in larger cohort studies within different ethnicities and different ALL protocols adjusted for other contemporary validated prognostic factors in childhood ALL.
Subject(s)
MicroRNAs/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Biomarkers, Tumor/genetics , Child , Humans , MicroRNAs/biosynthesisABSTRACT
Aggresomes are transient microtubule-dependent inclusion bodies that sequester misfolded proteins and are ultimately removed by autophagy. Here we report the generation of a choroid plexus carcinoma cell line; Children's Cancer Hospital Egypt (CCHE)-45, which is characterized by the constitutive formation of aggresomes. When examining the autophagy pathway as the main route for aggresomes clearance, CCHE-45 cells displayed increased autophagy flux mediated by MAP1LC3B. MAP1LC3A-Variant1 gene expression was silenced by promoter methylation. Restoring MAP1LC3A-Variant1 expression resulted in the formation of MAP1LC3A positive autophagosmes and the disruption of the aggresomes' vimentin cage independent of MAP1LC3B positive autophagosomes. Our data supports the notion that basal quality control autophagy and vimentin cage clearance in CCHE-45 are mediated by MAP1LC3A. Hence we propose that absence of MAP1LC3A disrupts the autophagic pathway and leads to the failure of aggresome vimentin cage degradation. Consequently, this could represent a targetable pathway in autophagy-dependent cancers.
Subject(s)
Autophagy , Carcinoma/genetics , Choroid Plexus Neoplasms/genetics , Microtubule-Associated Proteins/genetics , Vimentin/metabolism , Adolescent , Autophagosomes/metabolism , Carcinoma/metabolism , Carcinoma/pathology , Cell Line, Tumor , Cells, Cultured , Child , Choroid Plexus Neoplasms/metabolism , Choroid Plexus Neoplasms/pathology , Female , Gene Silencing , HEK293 Cells , Humans , Male , Microtubule-Associated Proteins/metabolismABSTRACT
BACKGROUND: Acute lymphocytic leukemia (ALL) is the most common pediatric cancer. The exact cause is not known in most cases, but past epidemiological research has suggested a number of potential risk factors. This study evaluated associations between environmental and parental factors and the risk for ALL in Egyptian children to gain insight into risk factors in this developing country. METHODS: We conducted a case-control design from May 2009 to February 2012. Cases were recruited from Children's Cancer Hospital, Egypt (CCHE). Healthy controls were randomly selected from the general population to frequency-match the cumulative group of cases by sex, age groups (<1; 1 - 5; >5 - 10; >10 years) and region of residence (Cairo metropolitan region, Nile Delta region (North), and Upper Egypt (South)). Mothers provided answers to an administered questionnaire about their environmental exposures and health history including those of the father. Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated using logistic regression with adjustment for covariates. RESULTS: Two hundred ninety nine ALL cases and 351 population-based controls frequency-matched for age group, gender and location were recruited. The risk of ALL was increased with the mother's use of medications for ovulation induction (ORadj = 2.5, 95 % CI =1.2 -5.1) and to a lesser extend with her age (ORadj = 1.8, 95 % CI = 1.1 - 2.8, for mothers ≥ 30 years old). Delivering the child by Cesarean section, was also associated with increased risk (ORadj = 2.01, 95 % CI =1.24-2.81). CONCLUSIONS: In Egypt, the risk for childhood ALL appears to be associated with older maternal age, and certain maternal reproductive factors.
