NF‐κB activation in development and progression of cancer

Nuclear factor‐κΒ (NF‐κB) binds specifically to NF‐κB‐binding sites (κB sites, 5′‐GGGRNNYYCC‐3′; R, purine; Y, pyrimidine; N, any nucleotide) present in enhancer regions of various genes. Binding of various cytokines, growth factors and pathogen‐associated molecular patterns to specific receptors activates NF‐κB and expression of genes that play critical roles in inflammation, innate and acquired immunity, bone remodeling and generation of skin appendices. Activation of NF‐κB is also involved in cancer development and progression. NF‐κB is activated in cells that become malignant tumors and in cells that are recruited to and constitute the tumor microenvironment. In the latter scenario, the TLR‐TRAF6‐NF‐kB pathways seem to play major roles, and NF‐κB activation results in production of cytokines, which in turn induce NF‐κB activation in premalignant cells, leading to expression of genes involved abnormal growth and malignancy. Furthermore, NF‐κB activation is involved in bone metastasis. Osteoclasts, whose generation requires the RANK‐TRAF6‐NF‐κB pathways, release various growth factors stored in bone, which results in creation of microenvironment suitable for proliferation and colonization of cancer cells. Therefore, NF‐κB and molecules involved its activation, such as TRAF6, are attractive targets for therapeutic strategies against cancer. ( Cancer Sci 2007; 98: 268–274)