Abstract
Genetic studies describing a link between cancer and inflammation have increased recently. Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes. NF-κB is persistently activated in several types of tumors. However, NF-κB has a distinct role in cancer cells and in inflammatory cells. While in tumor cells NF-κB controls cell survival, in inflammatory cells NF-κB activates genes that encode pro-inflammatory cytokines which further act in a paracrine manner within the tumor microenvironment to contribute to tumorigenesis. Inactivation of NF-κB can also reduce chemoresistance and radioresistance of cancer cells. Therefore, specific NF-κB inhibition in combination with cytotoxic drugs and/or irradiation represents a very promising strategy for cancer therapy.
Highlights
Genetic studies describing a link between cancer and inflammation have increased recently
It is known that nuclear factor-κB (NF-κB) has multiple critical roles in the regulation of immune responses and influences gene expression events that impact cell survival, differentiation, and proliferation
The first functional genetic in vivo evidence of NF-κB having a direct and indirect role in tumorigenesis came from murine model of colitis-associated carcinogenesis (CAC) when IKKβ was deleted in intestinal epithelial cells (IECs)—Which are the cells that undergo malignant progression—Or in myeloid cells [13]
Summary
NF-κB was first described as a B-cell-specific transcription factor that binds the κB site in the immunoglobulin (Ig) κ light chain enhancer region. The family of NF-κB proteins consists of five members, p50 (p105), p52 (p100), p65 (RelA), c-Rel, and RelB, encoded by the genes NF-κB1, NF-κB2, RELA, Cancers 2011, 3. NF-κB dimers bind to κB sites within the promoters/enhancers of target genes and regulate transcription through the recruitment of co-activators and co-repressors. The transcription activation domain (TAD) necessary for the positive regulation of gene expression is present only in p65, c-Rel, and. Because p50 and p52 lack TADs, they can repress transcription unless associated with a TAD-containing NF-κB family member or other proteins capable of co-activator recruitment [1]. Constitutive binding of p50 or p52 homodimers to κB sites on NF-κB-responsive promoters may act to check NF-κB transactivation until displaced by transcriptionally competent NF-κB dimers
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