Signaling Pathways Altered in Hepatic Cancer Stem Cells. Wnt/β-catenin, PI3K/PTEN/AKT, TGF-β/IGF-2R and IL-6/IL-6R/gp130 signaling pathways have been shown to be activated in HCC. Activation of the Wnt pathway results in β-catenin accumulation in the cytosol and translocation into the nucleus, where β-catenin forms two major protein-DNA complexes. 1) β-catenin/TCF/LEF is a classic complex of Wnt/β-catenin pathway that mediates Wnt target genes expression, e.g. EpCAM and miR-181; 2) EpICD/FHL2/β-catenin/LEF1-DNA complex represents a cross-talk of Wnt/β-catenin with EpCAM signaling pathway . Cleavage of EpCAM by TACE and PS-2 releases EpICD into cytosol which in turn translocates into the nuclues with β-catenin and FHL2, where EpICD/FHL2/β-catenin forms protein-DNA complex with LEF1and regulates EpCAM target genes expression, e.g. cyclin D1, c-Myc andd miR-181. AKT is activated by two phosphorylation sitess Thr308 and Ser473. Phosphorylation of Thr308 is promoted by PI3K and suppressed by PTEN. Activated AKT induces cell survival through the suppressive phosphorylation of BAD and Caspase 9, two apoptosis mediators in unphophorylated status. AKT also acts as a cell cycle progression regulator through activating the mTOR pathway . Two oncogenic pathways PI3K/PTEN/AKT and Wnt/β-catenin may be interconnected to promote stemness and carcinogenesis. Loss of IGF-2R impacts cell proliferation by accumulating IGF-2 mitogen and activation of TGF-β signaling.