RNA-binding protein PUM2 promotes T-cell acute lymphoblastic leukemia via competitively binding to RBM5 3'UTR with miR-28-5p.

OBJECTIVE: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, and T-ALL patients are prone to early disease relapse and suffer from poor outcomes. The crucial function of RNA-binding proteins (RBPs) has been reported in the progression of cancers by regulating the expression of transcripts. This study aimed to reveal the role and molecular regulatory mechanism of RBP Pumilio2 (PUM2) in T-ALL. METHODS: The expression of genes was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The viability, proliferation, and apoptosis of T-ALL cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine, and flow cytometry analysis. Luciferase reporter, RNA pulldown, and RNA immunoprecipitation assays were performed to confirm the binding of PUM2 to RBM5. The combination between RNA-binding motif protein 5 (RBM5) and microRNA (miR)-28-5p was validated using luciferase reporter assay. RESULTS: Our data revealed that PUM2 was highly expressed in T-ALL blood samples and cell lines. PUM2 knockdown suppressed the proliferation but accelerated the apoptosis of T-ALL cells in vitro. Additionally, RBM5 exhibited a low expression level in T-ALL samples and cells. PUM2 negatively regulated RBM5 via targeting its 3'untranslated region (3'UTR). Moreover, PUM2 competitively bound to RBM5 3'UTR with miR-28-5p. Rescue experiments showed that RBM5 knockdown reversed the anti-tumor effects mediated by PUM2 knockdown in T-ALL cells. CONCLUSION: PUM2 plays as a novel oncogenic RBP in T-ALL by competitively binding to RBM5 mRNA with miR-28-5p.

Neuroprotective potential of imatinib in global ischemia-reperfusion-induced cerebral injury: possible role of Janus-activated kinase 2/signal transducer and activator of transcription 3 and connexin 43.

The present study was aimed to explore the neuroprotective role of imatinib in global ischemia-reperfusion-induced cerebral injury along with possible mechanisms. Global ischemia was induced in mice by bilateral carotid artery occlusion for 20 min, which was followed by reperfusion for 24 h by restoring the blood flow to the brain. The extent of cerebral injury was assessed after 24 h of global ischemia by measuring the locomotor activity (actophotometer test), motor coordination (inclined beam walking test), neurological severity score, learning and memory (object recognition test) and cerebral infarction (triphenyl tetrazolium chloride stain). Ischemia-reperfusion injury produced significant cerebral infarction, impaired the behavioral parameters and decreased the expression of connexin 43 and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in the brain. A single dose administration of imatinib (20 and 40 mg/kg) attenuated ischemia-reperfusion-induced behavioral deficits and the extent of cerebral infarction along with the restoration of connexin 43 and p-STAT3 levels. However, administration of AG490, a selective Janus-activated kinase 2 (JAK2)/STAT3 inhibitor, abolished the neuroprotective actions of imatinib and decreased the expression of connexin 43 and p-STAT3. It is concluded that imatinib has the potential of attenuating global ischemia-reperfusion-induced cerebral injury, which may be possibly attributed to activation of JAK2/STAT3 signaling pathway along with the increase in the expression of connexin 43.

Clinical evaluation of the function of hypothalamo-pituitary-thyroid axis in children with central nervous system infections.

BACKGROUND: It is well known that certain non-thyroidal critical illness may lead to euthyroid sick syndrome(ESS). There are little reports about the change of thyroid hormone in the children's central nervous system (CNS) infections. RESULTS: The results of serum TT3, TT4 and TSH in these children were compared with those in 20 cases of healthy adults and 20 cases of adults with primary hypothyroidism. Serum T3 and T4 were decreased in 34/78 children with CNS infections, T3 and T4 were much lower than those of healthy adult (p < 0.05), but still higher than that of the primary hypothyroidism (p < 0.05), and TSH levels were not significant differences among children with CNS infections and children with non-CNS infections (p > 0.05). Low T3 and T4 levels in serum and cerebrospinal fluid(CSF)were predominant in children with serious infections of CNS, 31/34 (percent 91.17) cases of serious CNS infection had low serum TT3 and/or TT4. The low T3 with low T4 was seen in 14/34 children of severe CNS infections, 3 of them died. The levels of CSF T3 (X ± SD = 0.39 ± 0.47 ng/ml) and T4 (x ± SD = 1.02 ± 1.27 ug/dl) in the serious CNS infections were lower than that of non-CNS infections T3 (x ± SD = 0.93 ± 1.23 ng/ml), and T4 (x ± SD = 2.42 ± 1.70 ug/dl), 7 died children were all in the subjects of low T3 and/or low T4. In 22 children with non-CNS infections, serum T3 and T4 levels were lower than that of healthy adult, but have not significant difference(p > 0.05). CONCLUSIONS: These results suggest that detection of TT3, TT4 and TSH in serum and/or CSF simultaneous or alone in analyses would be valuable in correctly judging thyroid function and evaluating the prognosis of the children with infections of CNS. Measuring a little amount of blood (1 ml)or CSF required for this method is a simple, convenient and accurate method.