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Figure 4. p53 family proteins and liver progenitor/stem cell transformation. A: the origin of cancer stem cells (CSCs) in HCC. CSCs and liver cancer cells can originate from: (1) hepatic progenitor cells (HPCs) chronically activated by the persistent intrahepatic inflammation sustained by viral infections (HBV, HDV, HCV), alcohol consumption and metabolic disorders; (2) hepatocytes undergoing dedifferentiation and expressing stem-related genes (such as Nanog). According to the currently available knowledge, ΔNp73 expression levels and its role in the different steps are highlighted; B: crosstalk between IGF1R, Nanog and p53 family in liver cancer cells. IGF1R repression by wtp53 and TAp73 and NANOG repression by wtp53 inhibit the dedifferentiation of liver cancer cells. In presence of the N-terminal truncated isoforms Δ40p53 or ΔNp73, wtp53 activity is inhibited, IGF1R and NANOG are expressed and activate a positive feedback loop. By activating AURKA-aPKCζ kinase cascade Nanog induces NumB phosphorylation and disrupts the p53-NumB interaction thus allowing Mdm2-mediated polyubiquinilation and proteasome degradation of p53. The loss of p53 function, achieved either by expression of ΔN isoforms or p53 degradation, favors stemness features, increased proliferation, dissemination and chemoresistance of liver cancer cells