Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia

Abstract

Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols.

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease

“…11 Recent studies observed an interaction between Notch3 and p65/NF-kB to regulate T cell function under control conditions or in disease. 23,24 A pathogenic role for the Notch3 receptor was first described in CADASIL syndrome. CADASIL syndrome is a systemic arteriopathy attributed to Notch3 mutations that induce an accumulation of the extracellular domain of Notch3 in the vascular smooth muscle cells of the media layer of arteries.…”

Loss of Notch1-dependent p21Waf1/Cip1expression influences the Notch1 outcome in tumorigenesis

“…Notch1 blocking antibodies MHN1-519 were purchased from BioLegend, and the treatment was performed as previously described. 55,56 Notch1 Val1744, Fbxw7 were purchased from Cell Signaling Technology. Blots were incubated for 2 h at room temperature or with an anti-Notch1 Val1744 (Cell Signaling Technology) overnight at 4 °C according Cell Signaling manufacturer's instruction.…”

Beyond circulating microRNA biomarkers: Urinary microRNAs in ovarian and breast cancer

“…This can occur via a perfect complimentary binding of the miRNA to the target mRNA (endonucleolytic cleavage of the mRNA) or by an imperfect complimentary binding to the target mRNA (translation repression). 32 Due to their cell cycle interference, miRNAs are involved either as oncogenes or as oncosuppressors in the pathogenesis of a huge variety of human cancers such as lung cancer, 33,34 prostate cancer, 35 colorectal cancer, 36,37 leukemia, [38][39][40] gliomas 41 and medulloblastoma, 42 diffuse large B-cell lymphoma, 43 hepatocellular carcinoma (HCC), 44 gastric cancer, 45,46 osteosarcoma, 47 renal cell carcinoma, 48 BC, 49 and OC. 50 Particularly, their presence in the blood has been shown to be associated with histology, clinical stage, survival, and oncogenic expression in OC and BC.…”