Animal Models of Colitis-Associated Carcinogenesis

Figure 3

Wnt signaling plays central role in embryogenesis and human diseases including cancers. Wnt ligands to 7-transmembrane domain receptor Frizzled, which transactivates EGFR signaling by MMP-mediated release of soluble EGFR ligands. Activated EGFR transactivates β-catenin via receptor tyrosine kinase-PI3K/Akt pathway, and β-catenin also forms heterodimer with EGFR and further activate EGF pathway. Direct activation of EGFR utilizing EGF-family ligands induces CHI3L1 expression, which binds to a putative receptor on cell membrane and leads to PI3K-mediated phosphorylation of Akt followed by β-catenin transactivation. As shown in this figure, Wnt and EGFR pathways have been reported to closely interact in tumorigenesis by crosstalking and coactivating tumor progression. The activation of ASK1, following of TNF/TNFR1 and/or IL-1/IL-1R ligation, activates SAPK/JNK and MAPKp38 followed by increased production of MMPs and cytokines. NF-κB signal is also activated by TNF and IL-1, which is highly involved in the development of chronic colitis as well as colitis-associated cancer formation. The abbreviations used in this figure are: ASK-1, apoptosis signal-regulating kinase 1; ATF-2, activating transcription factor 2; BAD, Bcl2-antagonist of cell death; Bcl2, B-cell lymphoma 2; CHI3L1, chitinase 3-like-1; EGF, epidermal growth factor; Elk-1, Ets like gene 1; GSK3β, glycogen synthesis kinasse 3 beta, Lef-1/TCF, lymphoid enhancer-binding factor-1/Tcell factor; IKK, IκB kinase; IRAK, IL-1 receptor associated factor; LPR5/6, lipoprotein-related receptor 5 and 6; PI3K, phosphoinositide 3-kinase; SAPK/JNK, stress-activated protein kinase/c-Jun NH2-terminal kinase; TBP, TATA-binding protein; TNFR1; Tumor necrosis factor receptor 1; TRADD, TNF receptor 1-associated death domain; TRAF, TNF receptor associated factor.