NF-κB in cancer: from innocent bystander to major culprit

Karin, Michael; Cao, Yixue; Greten, Florian R.; Li, Zhiwei

doi:10.1038/nrc780

Cited by 2,348 publications

(2,053 citation statements)

References 96 publications

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“…Consistent with a role for IKKa in promoting cyclin D1 transcription, Karin et al (2002) have found that during mammary gland development IKKa is required for RANK signaling and cyclin D1 expression. Other mechanisms whereby NF-kB may potentiate cancer cell growth is through its reported requirement for the upregulation of HIF-1a (Jung et al, 2003) and its regulation of c-myc transcription (see Baldwin 2001;Karin et al, 2002). Consistent with these reports, tumor growth in several mouse xenograft models is impaired when NF-kB is inhibited (see Reuther et al, 1998;Baldwin, 2001;Karin et al, 2002).…”

Section: Growth and Proliferationsupporting

confidence: 55%

“…Furthermore, IKKa has been proposed to play a role in cyclin D1 transcription through a T-cell factor site in the promoter, via its ability to control b-catenin phosphorylation (Albanese et al, 2003). Consistent with a role for IKKa in promoting cyclin D1 transcription, Karin et al (2002) have found that during mammary gland development IKKa is required for RANK signaling and cyclin D1 expression. Other mechanisms whereby NF-kB may potentiate cancer cell growth is through its reported requirement for the upregulation of HIF-1a (Jung et al, 2003) and its regulation of c-myc transcription (see Baldwin 2001;Karin et al, 2002).…”

Section: Growth and Proliferationmentioning

confidence: 71%

“…As described below, recent evidence has accumulated from a large variety of human malignancies indicating a role for NF-kB in promoting oncogenic conversion and in facilitating later stage tumor properties such as metastasis (Rayet and Ge´linas, 1999;Baldwin 2001;Karin et al, 2002).…”

Section: Linking Nf-jb With Oncogenesismentioning

confidence: 99%

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Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

2006

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Section: Growth and Proliferationsupporting

confidence: 55%

Section: Growth and Proliferationmentioning

confidence: 71%

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Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

2006

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“…The NF-κB system comprises a family of transcription factors that are held inactive in the cytoplasm by a family of inhibitory proteins known as IκBs 75 . These inhibitors are ubiquitylated and degraded by a phosphorylation event that is triggered by the IκB kinase (IKK).…”

mentioning

confidence: 99%

MET signalling: principles and functions in development, organ regeneration and cancer

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,060

1,076

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The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.Throughout embryogenesis, cells bud off from developing tissues and move outwards to shape and pattern the complex architecture of prospective organs 1 . A similar process occurs in adult life during wound healing and tissue repair, when lingering cells migrate into injury sites to recreate the pre-existing structures 2 . The acquisition of cell motility is necessary, but not sufficient, for this event. Cells that detach from their neighbours must elude anoikis, a form of apoptotic cell death that occurs when cells lose adhesion with the extracellular matrix 3 . Moreover, migratory cells undergo extensive mitotic divisions to produce 'founder populations', which settle in newly forming organs during development or colonize worn tissues during repair 4,5 . The normal phases of embryogenesis and organ regeneration strongly resemble the pathological process of tumour invasiveness: similarly to cells at the wound edge, cells at the tumour's leading front disrupt intercellular contacts and infiltrate the adjacent surroundings, where they resist anoikis and grow before lodging in the blood vessels for systemic dissemination 6 . This resemblance is not simply a biological correlate, it has a common mechanistic basis: cancer cells resurrect the latent schemes of cellular reorganization, which are usually confined to embryonic development and damaged adult organs, and leverage them to become competent for metastasization 7 . The activities -motility, survival and proliferation -that occur in developing, injured and neoplastic tissues embody a biological programme that is defined as 'invasive growth' 8 . This is triggered by extracellular stimuli that regulate the activity of several transcription factors that, in turn, modulate the expression of a number of proteins, ranging from cytoskeletal and cell-cell junctional components to cell cycle regulators and anti-apoptotic effectors 9, 10 . One major environmental inducer of invasive growth is hepatocyte growth factor (HGF, also known as scatter factor), the ligand for the MET tyrosine kinase receptor (also known as the HGF receptor) 11,12,13,14,15,16,17,18,19,20 (Box 1). ...

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“…It is assembled as a hetero-or homodimer from the structurally closely related subunits RelA/p65, c-Rel, RelB, p50 and p52 (Karin et al, 2002).…”

mentioning

confidence: 99%

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

et al. 2007

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Activation of nuclear factor-kB (NF-kB) signaling was observed in pancreatic adenocarcinoma cell lines and tumours. However, information on the expression of RelA/p65, the major transcription activating NF-kB subunit, in these carcinomas and possible correlations thereof with NF-kB activation and patient survival is not available. To provide this missing translational link, we analysed expression of RelA/p65 in 82 pancreatic adenocarcinomas by immunohistochemistry. Moreover, we measured activation of the NF-kB pathway in 11 tumours by quantitative PCR for NF-kB target genes. We observed strong cytoplasmic or nuclear expression of RelA/p65 in 42 and 37 carcinomas, respectively. High cytoplasmic and nuclear expression of RelA/p65 had negative prognostic impact with 2-year survival rates for patients without cytoplasmic or nuclear RelA/p65 positivity of 41 and 40% and rates for patients with strong cytoplasmic or nuclear RelA/p65 expression of 22 and 20%, respectively. High RelA/p65 expression was correlated to increased expression of NF-kB target genes. The observation that high expression of RelA/p65 is correlated to an activation of the NF-kB pathway and indicates poor patient survival identifies a patient subgroup that might particularly benefit from NF-kB-inhibiting agents in the treatment of pancreatic cancer. Based on our findings, this subgroup could be identified by applying simple immunohistochemical techniques.

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NF-κB in cancer: from innocent bystander to major culprit

Cited by 2,348 publications

References 96 publications

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

MET signalling: principles and functions in development, organ regeneration and cancer

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

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