Constitutive nuclear factor-KB (NF-KB) activation is observed in androgen-independent prostate cancer and represents a predictor for biochemical recurrence after radical prostatectomy. Dietary agents such as pomegranate extract (PE) have received increasing attention as potential agents to prevent the onset or progression of many malignancies, including prostate cancer. Here, we show that PE inhibited NF-KB and cell viability of prostate cancer cell lines in a dose-dependent fashion in vitro. Importantly, maximal PE-induced apoptosis was dependent on PE-mediated NF-KB blockade. In the LAPC4 xenograft model, PE delayed the emergence of LAPC4 androgen-independent xenografts in castrated mice through an inhibition of proliferation and induction of apoptosis. Moreover, the observed increase in NF-KB activity during the transition from androgen dependence to androgen independence in the LAPC4 xenograft model was abrogated by PE. Our study represents the first description of PE as a promising dietary agent for the prevention of the emergence of androgen independence that is driven in part by heightened NF-KB activity. [Mol Cancer Ther 2008;7(9):2662 -71]
SUMMARY The biochemical mechanisms that underlie hypoxia-induced NF-κB activity have remained largely undefined. We found that prolonged hypoxia-induced NF-κB activation is restricted to cancer cell lines infected with high risk human papilloma virus (HPV) serotypes. The HPV-encoded E6 protein is necessary and sufficient for prolonged hypoxia-induced NF-κB activation in these systems. The molecular target of E6 in the NF-κB pathway is the CYLD lysine 63 (K63) deubiquitinase, a negative regulator of the NF-κB pathway. Specifically, hypoxia stimulates E6-mediated ubiquitination and proteasomal degradation of CYLD. Given the established role of NF-κB in human carcinogenesis, these findings provide a potential molecular/viral link between hypoxia and the adverse clinical outcomes observed in HPV-associated malignancies. SIGNIFICANCE Intratumoral hypoxia is a critical factor in the poor clinical outcomes of human malignancies, most notably cervix and head and neck cancers. We found that prolonged hypoxia-induced NF-κB activation is not a generalized phenomenon amongst cancer cells but rather is restricted to human papilloma (HPV)-positive cancers, such as cervix and head and neck cancers. Under hypoxic conditions, the HPV-encoded E6 protein inactivates the CYLD tumor suppressor, a negative regulator of the NF-κB pathway and thereby allows for unrestricted activation of NF-κB. Because NF-κB-induced genes promote survival, proliferation, and angiogenesis, our findings illustrate how a common human virus adapts to hypoxia and helps account for the aggressive tumor biology associated with hypoxia.
The critical downstream signaling consequences contributing to renal cancer as a result of loss of the tumor suppressor gene von Hippel-Lindau (VHL) have yet to be fully elucidated. Here, we report that VHL loss results in an epithelial to mesenchymal transition (EMT). In studies of paired isogenic cell lines, VHL silencing increased the levels of N-cadherin and vimentin and reduced the levels of E-cadherin relative to the parental VHL + cell line, which displayed the opposite profile. VHL + cells grew as clusters of cuboidal and rhomboid cells, whereas VHL-silenced cells took on an elongated, fibroblastoid morphology associated with a more highly invasive character in Matrigel chamber assays. Based on earlier evidence that VHL loss can activate NF-κB, a known mediator of EMT, we tested whether NF-κB contributed to VHL-mediated effects on EMT.On pharmacologic or molecular inhibition of NF-κB, VHL-silenced cells regained expression of E-cadherin, lost expression of N-cadherin, and reversed their highly invasive phenotype. Introducing a pVHL-resistant hypoxiainducible factor 1α (HIF1α) mutant (HIFα M ) into VHL + cells heightened NF-κB activity, phenocopying EMT effects produced by VHL silencing. Conversely, inhibiting the heightened NF-κB activity in this setting reversed the EMT phenotype. Taken together, these results suggest that VHL loss induces an EMT that is largely dependent on HIFα-induced NF-κB. Our findings rationalize targeting the NF-κB pathway as a therapeutic strategy to treat renal tumors characterized by biallelic VHL inactivation. Cancer Res; 70(2); 752-61. ©2010 AACR.
Clear cell renal cell carcinomas (RCC), the major histologic subtype of RCC accounting for more than 80% of cases, are typified by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. Although accumulation of hypoxia-inducible factor alpha (HIF-a) is the most well-studied effect of VHL inactivation, direct inhibition of HIFa or restoration of wild-type pVHL protein expression has not proved readily feasible, given the limitations associated with pharmacologic targeting of transcription factors (i.e
Objective To report our experience in the reconstruction of soft tissue defects in the hand with a free anterolateral thigh deep fascia flap and describe the clinical outcomes. Methods This study was a retrospective trial. From November 2016 to January 2020, six patients (four men and two women) with soft tissue defects in the hand were included in this study. The average age of the patients was 33.7 ± 12.7 years (range, 20 to 50 years). All patients underwent reconstructions with free anterolateral thigh deep fascia flaps. Relevant clinical characteristics were recorded prior to surgery. The size and thickness of the deep fascia flap and the thickness of the skin were measured intraoperatively. The survival of the flaps and skin grafts and the occurrence of infection were recorded after the operation. At follow‐up, donor site complications and postoperative effects were evaluated according to the outcome satisfaction scale. The pain in the injured hand was assessed using the visual analog scale. Results The average body mass index (BMI) was 26.6 ± 1.7 kg/m2 (range, 23.9 to 28.7 kg/m2). The defect sizes ranged from 5 cm × 5 cm to 13 cm × 8 cm (average, 53.1 ± 27.9 cm2). The six anterolateral thigh deep fascia flaps ranged from 7 cm × 6 cm to 14 cm × 9 cm in size (average, 71.8 ± 29.1 cm2). The thicknesses of skin ranged from 25 mm to 40 mm (average, 32.5 ± 4.8 mm), and the thicknesses of the deep fascia flaps ranged from 2 mm to 3 mm (average, 2.5 ± 0.5 mm). After the operation, the blood supply of the deep fascia flap was normal in all cases. The second‐stage skin grafts of most patients survived completely. The skin graft in one case was partially necrotic and healed after a dressing change. No infection occurred. At follow‐up (average, 16.3 ± 6.9 months), there was only a linear scar and no loss of sensation at the donor site of each patient. According to the outcome satisfaction scale, the outcome satisfaction score ranged from 6 to 8 (average, 7.2 ± 0.9), all of which were satisfactory. Apart from one patient who reported mild pain, all the other patients reported no pain. Three typical cases are presented in this article. Conclusions The free anterolateral thigh deep fascia flap, which is suitable for reconstruction of soft tissue defects in the hand, can provide very good outcomes both functionally and aesthetically.
<div>Abstract<p>The critical downstream signaling consequences contributing to renal cancer as a result of loss of the tumor suppressor gene <i>von Hippel-Lindau</i> (<i>VHL</i>) have yet to be fully elucidated. Here, we report that <i>VHL</i> loss results in an epithelial to mesenchymal transition (EMT). In studies of paired isogenic cell lines, <i>VHL</i> silencing increased the levels of N-cadherin and vimentin and reduced the levels of E-cadherin relative to the parental VHL<sup>+</sup> cell line, which displayed the opposite profile. VHL<sup>+</sup> cells grew as clusters of cuboidal and rhomboid cells, whereas VHL-silenced cells took on an elongated, fibroblastoid morphology associated with a more highly invasive character in Matrigel chamber assays. Based on earlier evidence that <i>VHL</i> loss can activate NF-κB, a known mediator of EMT, we tested whether NF-κB contributed to VHL-mediated effects on EMT. On pharmacologic or molecular inhibition of NF-κB, VHL-silenced cells regained expression of E-cadherin, lost expression of N-cadherin, and reversed their highly invasive phenotype. Introducing a pVHL-resistant hypoxia-inducible factor 1α (HIF1α) mutant (HIFα<sup>M</sup>) into VHL<sup>+</sup> cells heightened NF-κB activity, phenocopying EMT effects produced by VHL silencing. Conversely, inhibiting the heightened NF-κB activity in this setting reversed the EMT phenotype. Taken together, these results suggest that <i>VHL</i> loss induces an EMT that is largely dependent on HIFα-induced NF-κB. Our findings rationalize targeting the NF-κB pathway as a therapeutic strategy to treat renal tumors characterized by biallelic <i>VHL</i> inactivation. Cancer Res; 70(2); 752–61</p></div>
Supplementary Figure Legends 1-3 from NF-κB–Dependent Plasticity of the Epithelial to Mesenchymal Transition Induced by <i>Von Hippel-Lindau</i> Inactivation in Renal Cell Carcinomas
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