Figure 4.

Mucins, chronic inflammation and cancer. In this proposed model of the association of mucins with chronic inflammation and cancer, the production of inflammatory cytokines by immune effector cells activates transcription factors, for example nuclear factor-κB (NF-κB), signal transducer and activator of transcription 1 (STAT1) and STAT3, in epithelial cells. In turn, these transcription factors upregulate mucin expression to enhance the mucous barrier and protect the epithelial layer. Mucin 2 (MUC2) limits the inflammatory response at the apical membrane and inhibits transformation. Upregulation of the MUC1 and MUC4 transmembrane mucins similarly contributes to the protective barrier and loss of polarity in the epithelial stress response. Activation of MUC1 is associated with targeting of the MUC1 C-terminal transmembrane subunit (MUC1-C) to the nucleus, where it promotes a gene programme for proliferation and survival. Targeting of MUC1-C to the mitochondria also blocks cell death to prevent loss of the epithelial barrier. However, with chronic inflammation and prolonged stimulation of this protective response, epithelial cells may become susceptible to the accumulation of genetic mutations that induce transformation in a setting with downregulation of pathways that would otherwise protect against oncogenic events. IL-6, interleukin-6; IFNγ, interferon-γ; TNFα, tumour necrosis factor-α. Reprinted from¹⁴⁸, with permission.