fig1

Figure 1. Molecular modulatory signaling involved in iCCA initiation. The figure represents the main known morphogenetic mechanisms involved in cell transdifferentiation towards iCCA. The interaction between YAP/TAZ, β-catenin and NOTCH signaling pathways stimulate the activation of malignant mechanisms in hepatic epithelial cells. These signaling pathways can be modulated positively by DNMT1 expression or negatively by FBXW7 and H3K9me2. The transcription factors, once transported into the nucleus, can bind to the specific binding sites TEADs, TCF/LEF and RBPj, for YAP/TAZ, β-catenin and NICD, respectively, activating the transcription of downstream genes involved in tumor proliferation and invasiveness and fibroinflammation. blue lines: inhibition; DNMT1: DNA methyltransferase 1; FBXW7: F-box and WD repeat domain containing 7; H3K9me2: G9a-derived dimethylated histone H3 lysine 9; NICD: Notch Intracellular domain; P: phosphorylation; Red arrow: activation; RBPj: recombination signal binding protein for immunoglobulin kappa J region; YAP: yes-associated protein; TAZ: transcriptional coactivator with PDZ-binding motif; TEAD: transcriptional enhanced associate domain; TCF/LEF: T cell factor/lymphoid enhancer factor family; YAP: yes-associated protein.