The NF-B family mediates immune and inflammatory responses. In many cancers, NF-B is constitutively activated and induces the expression of genes that facilitate tumorigenesis. ING4 is a tumor suppressor that is absent or mutated in several cancers. Herein, we demonstrate that in human gliomas, NF-B is constitutively activated, ING4 expression is negligible, and NF-B-regulated gene expression is elevated. We demonstrate that an ING4 and NF-B interaction exists but does not prevent NF-B activation, nuclear translocation, or DNA binding. Instead, ING4 and NF-B bind simultaneously at NF-B-regulated promoters, and this binding correlates with reductions in p65 phosphorylation, p300, and the levels of acetylated histones and H3-Me3K4, while enhancing the levels of HDAC-1 at these promoters. Using a knockdown approach, we correlate reductions in ING4 protein levels with increased basal and inducible NF-B target gene expression. Collectively, these data suggest that ING4 may specifically regulate the activity of NF-B molecules that are bound to target gene promoters.
Malignant gliomas are diffusively infiltrative and remain among the deadliest of all cancers. NF-κB is a transcription factor that mediates cell growth, migration and invasion, angiogenesis and resistance to apoptosis. Normally, the activity of NF-κB is tightly regulated by numerous mechanisms. However, in many cancers, NF-κB is constitutively activated and may function as a tumor promoter. Herein, we show that in gliomas, NF-κB is constitutively activated and the levels of cIAP2, Bcl-2, Bcl-xL and Survivin are elevated. These genes are regulated by NF-κB and can inhibit apoptosis. To understand the potential role of NF-κB p65 in suppressing apoptosis, we generated human glioma cell lines that inducibly express shRNA molecules specific for p65. We demonstrate that in the absence of p65, TNF-α induced cIAP2 expression is significantly reduced while the levels of Bcl-2, Bcl-xL and Survivin are not affected. These data suggest that of these genes, only cIAP2 is a direct target of p65. Using RT-PCR and chromatin immunoprecipitation assays, we have confirmed that cIAP2 is a transcriptional target of NF-κB p65. As a consequence of reduced p65 and cIAP2 levels, we demonstrate that the levels of RIP poly-ubiquitination are reduced, and that p65-deficient glioma cells are more sensitive to the cytotoxic effects of TNF-α than glioma cells expressing p65. Specifically, in the presence of TNF-α, glioma cells lacking p65 showed cellular proliferation defects and underwent apoptosis. Moreover, glioma cells were similarly sensitized to the effects of TNF-α if the levels of cIAP2 were reduced through lentivirus shRNA expression. These data suggest that NF-κB and/or cIAP2 may be therapeutically relevant targets for the treatment of malignant gliomas.
Background Ganglion cysts are the most frequent soft tissue tumor encountered in the upper extremity and are commonly treated by aspiration or by surgical excision. Ultrasound is a promising addition to traditional aspiration, as it allows for visualization of the needle within the ganglion before aspiration. Questions Are ganglion cysts of the wrist less likely to reoccur if they are aspirated under ultrasound guidance versus “blind” aspiration without the use of ultrasound guidance? Does patient functionality change based on whether or not the cyst recurred? Patients and Methods In total, 52 patients were successfully contacted and recurrence rates were compared between those whose cyst was treated with ultrasound-guided (13 patients) with those whose cyst was treated with blind aspiration (39 patients). Mean follow-up time was 2.9 years. Results Recurrence rates were 69% (9 patients) and 74% (29 patients) for the ultrasound-guided and blind aspiration groups, respectively (p-value: 0.73), showing no significant difference in recurrences of wrist ganglion between the two groups. A metric of functionality (Quick–DASH [Disabilities of the Arm, Shoulder, and Hand]) revealed worse outcomes in patients who experienced return of ganglion cyst after aspiration versus those who did not. Conclusion Additional studies with improved sample sizes are needed to demonstrate the superiority of ultrasound-guided aspiration versus blind aspiration. Due to a high recurrence rate following aspiration (both ultrasound-guided and blinded), a lower threshold for surgical intervention is likely reasonable. Level of Evidence This is a Level IIIb study.
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