IKK/NF-kappaB and STAT3 pathways: central signalling hubs in inflammation-mediated tumour promotion and metastasis

Abstract

Our understanding of the molecular mechanisms that link inflammation and cancer has significantly increased in recent years. Here, we analyse genetic evidence indicating that the transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) have a central role in this context by regulating distinct functions in cancer cells and surrounding non-tumorigenic cells. In immune cells, NF-kappaB induces the transcription of genes that encode pro-inflammatory cytokines, which can act in a paracrine manner on initiated cells. By contrast, in tumorigenic cells, both NF-kappaB and STAT3 control apoptosis, and STAT3 can also enhance proliferation. Consequently, inflammation should be considered as a valuable target for cancer prevention and therapy.

Figure 1

NF-κB signalling. On ligand interaction with surface receptors, one of two NF-κB activation pathways can be elicited. Canonical signalling depends on IKKγ and IKKβ and induces the transcription of genes that regulate inflammation and cell survival. By contrast, non-canonical NF-κB activation is mostly involved in the regulation of B-cell development. BAFF, B-cell activating factor of the TNF family; IL, interleukin; IKK, IκB kinase; LTβ-R, lymphotoxin-β receptor; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end product; TLR, toll-like receptor; TNF, tumour necrosis factor.

Figure 2

STAT signalling. On binding of IL-6 or IL-11 to the α-subunit of their receptors—which is followed by receptor heterodimerization with the gp130 receptor—JAKs are activated and phosphorylate tyrosine residues in the cytoplasmic region of gp130, which lead to the recruitment of SHP2, STAT3 or STAT1 monomers. These STATs can bind to gp130 through their SH2 domains and become phosphorylated before their dimerization and translocation to the nucleus. Growth factors and non-receptor tyrosine kinases—such as SRC and ABL—can also activate STAT3 signalling. Growth factor receptors that are known to activate STAT3 include the epidermal growth factor receptors EGFR and HER2, vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor (PDGFR), insulin-like growth factor (IGFR), hepatocyte growth factor (HGFR) and fibroblast growth factor receptor (FGFR). ABL, Abelson leukaemia protein; gp130, glycoprotein of 130 kDa; IL, interleukin; JAK, Janus kinase; SRC, sarcoma kinase; STAT, signal transducer and activator of transcription.

Figure 3

IEC–myeloid cell cross-talk during colitis-associated cancer. NF-κB-regulated chemokine expression leads to the recruitment of immune cells that secrete pro-inflammatory cytokines such as IL-11 and the IKK/NF-κB-controlled TNFα, IL-1 and IL-6. These cytokines in turn induce STAT3 and NF-κB signalling in enterocytes. STAT3 controls the transcription of genes involved in both cell survival and proliferation, whereas NF-κB does not have an effect on proliferation. CCL, chemokine (C-C motif) ligand; CXCL, chemokine (C-X-C motif) ligand; HSP, heat shock protein; IEC, intestinal epithelial cell; IL, interleukin; IKK, IκB kinase; NF-κB, nuclear factor-κB; REG, regenerating islet-derived; STAT3, signal transducer and activator of transcription 3; TNFα, tumour necrosis factor-α.