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Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies.

ABSTRACT: The nuclear factor kappa B (NF?B) pathway is essential for many human cancers. Therapeutics such as bortezomib (Velcade™) that interfere with NF?B signaling are of great clinical interest. NF?B signaling, however, is multifaceted and variable among tissues, developmental and disease entities. Hence, targeted biomarkers of NF?B pathways are of prime importance for clinical research. We developed a novel real-time qPCR-based NF?B array. Only mechanistically validated NF?B targets were included. We then used random-forest classification to define individual genes and gene combinations within the NF?B pathways that define viral lymphoma subclasses as well as Kaposi sarcoma (KS). Few NF?B targets emerged that were universally present in all tumor types tested, underscoring the need for additional tumor-type specific biomarker discovery. (i) We uncovered tissue of origin-specific tumor markers, specifically CD69, CSF-1 and complement factor B (C1QBP) for primary effusion lymphoma (PEL); IL1-beta, cyclinD3 and CD48 for KS. We found that IL12, jun-B, msx-1 and thrombospondin 2 were associated with EBV co-infection in PEL. (ii) We defined the NF?B signature of Epstein-Barr virus (EBV) positive AIDS-associated Burkitt lymphoma (BL). This signature identified CCR5 as the key marker. (iii) This signature differed from EBV negative BL consistent with the idea that EBV not only activates NF?B activity but that this virus also reprograms NF?B signaling toward different targets.

SUBMITTER: Ramos JC

PROVIDER: S-EPMC3265660 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies.

Ramos Juan-Carlos JC Sin Sang-Hoon SH Staudt Michelle R MR Roy Debasmita D Vahrson Wolfgang W Dezube Bruce J BJ Harrington William W Dittmer Dirk P DP

International journal of cancer 20110829 11

The nuclear factor kappa B (NFκB) pathway is essential for many human cancers. Therapeutics such as bortezomib (Velcade™) that interfere with NFκB signaling are of great clinical interest. NFκB signaling, however, is multifaceted and variable among tissues, developmental and disease entities. Hence, targeted biomarkers of NFκB pathways are of prime importance for clinical research. We developed a novel real-time qPCR-based NFκB array. Only mechanistically validated NFκB targets were included. We ...[more]

PMID: 21792887

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Project description:Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been shown to have an effect similar to that of progranulin. Atsttrin has anti-inflammatory actions in multiple arthritis mouse models, and it protects against further arthritis development. However, whether Atsttrin has a role in neuroinflammation remains to be elucidated. In this study, we produced a neuroinflammatory mouse model by intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). Atsttrin (2.5 mg/kg) was administered via intraperitoneal injection every 3 days over a period of 7 days before intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). In addition, astrocyte cultures were treated with 0, 100 or 300 ng/mL lipopolysaccharide, with 200 ng/mL Atsttrin simultaneously. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction were performed to examine the protein and mRNA levels of inflammatory mediators and to assess activation of the nuclear factor kappa B signaling pathway. Progranulin expression in the brain of wild-type mice and in astrocyte cultures was increased after lipopolysaccharide administration. The protein and mRNA expression levels of tumor necrosis factor-α, interleukin-1β and inducible nitric oxide synthase were increased in the brain of progranulin knockout mice after lipopolysaccharide administration. Atsttrin treatment reduced the lipopolysaccharide-induced increase in the protein and mRNA levels of tumor necrosis factor-α, interleukin-1β, matrix metalloproteinase-3 and inducible nitric oxide synthase in the brain of progranulin knockout mice. Atsttrin also reduced the expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase 3 mRNA in lipopolysaccharide-treated astrocytes in vitro, and decreased the concentration of tumor necrosis factor a and interleukin-1β in the supernatant. Furthermore, Atsttrin significantly reduced the levels of phospho-nuclear factor kappa B inhibitor a in the brain of lipopolysaccharide-treated progranulin knockout mice and astrocytes, and it decreased the expression of nuclear factor kappa B2 in astrocytes. Collectively, our findings show that the anti-neuroinflammatory effect of Atsttrin involves inhibiton of the nuclear factor kappa B signaling pathway, and they suggest that Atsttrin may have clinical potential in neuroinflammatory therapy. The study was approved by the Animal Ethics Committee of Qilu Hospital of Shandong University, China (approval No. KYLL-2015(KS)-088) on February 10, 2015.

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Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies.

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Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies.

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