ABSTRACT
MicroRNAs have been implicated as important mediators of cancer cell homeostasis, and accumulating data suggest compelling roles for them in the apoptosis pathway. X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor and an important barrier to apoptotic cell death, but the mechanisms that determine the diverse range of XIAP expression seen in cancer remains unclear. In this study, we present evidence that miR-24 directly targets the 3'UTR of the XIAP messenger RNA (mRNA) to exert translational repression. Using a heuristic algorithm of bioinformatics analysis and in vitro screening, we identified miR-24 as a candidate regulator of XIAP expression. Array comparative genomic hybridization and spectral karyotype analysis reveal that genomic copy number loss at the miR-24 locus is concordant with the loss of endogenous miR-24 in cancer cells. Using a luciferase construct of the XIAP 3'UTR, we showed that miR-24 specifically coordinates to the XIAP mRNA. Interference with miR-24's binding of the critical seed region, resulting from site-directed mutagenesis of the 3'UTR, significantly abrogated miR-24's effects on XIAP expression. Moreover, miR-24 overexpression can overcome apoptosis resistance in cancer cells via downregulation of XIAP expression, and the resulting cancer cell death induced by tumor necrosis factor-related apoptosis-inducing ligand is executed by the canonical caspase-mediated apoptosis pathway. In summary, our data suggest a novel mechanism by which miR-24 directly modulates XIAP expression level and consequently the apoptosis threshold in cancer cells.
Subject(s)
Apoptosis/physiology , MicroRNAs/genetics , Neoplasms/genetics , Neoplasms/pathology , X-Linked Inhibitor of Apoptosis Protein/metabolism , 3' Untranslated Regions , Apoptosis/genetics , Cell Growth Processes/genetics , Cell Growth Processes/physiology , Cell Line, Tumor , Down-Regulation , HeLa Cells , Humans , MicroRNAs/metabolism , Neoplasms/metabolism , Transfection , X-Linked Inhibitor of Apoptosis Protein/geneticsABSTRACT
BACKGROUND: Sickle cell disease (SCD) is a common disease in Saudi Arabia, with a high prevalence in the Eastern and Southern regions. This study reports on 53 cases of SCD encountered in the Madina area. PATIENTS AND METHODS: In a retrospective study of 6000 pediatric patients, 53 children (0.88%) with sickle cell disease were admitted in the Maternity and Childrenâs Hospital at Madina, between November 1990 and October 1991. Of these, 39 patients (73.58%) were Saudis and 14 (26.41%) were non-Saudis. RESULTS: Thirty-six patients were homozygous SS and 17 were sickle thalassemic. The main causes of admission were vaso-occlusive crisis (77.35%), infection (67.92%), acute chest syndrome (22.64%), anemia (12.6%), and cerebrovascular accident (9.43%). The lowest and highest age groups recorded in this study were six months and 12 years, respectively. About 70% of the patients are still being followed up, and none of the patients has died. CONCLUSION: . This disease is one of the major causes of morbidity in this region of Saudi Arabia. Measures required include neonatal screening programs for the early detection of the disease, as well as research into new drugs to counter the disease.
