They also confirmed Estrogen Receptor Pathway that Notch1 is a bona fide oncogene in experimental liver cancer. Using a transgenic mouse model, Zender et al[116] proved that stable overexpression of Notch 1 in bipotential LSCs causes the formation of intrahepatic CCCs. Dill et al[121] and Cardinale et al[122] also reported that liver-specific expression

of the intracellular domain of Notch2 (N2ICD) in mice is sufficient to induce HCC formation, while DENN2ICD (diethylnitrosamine-induced HCCs with constitutive Notch2 signaling) mice develop large hepatic cysts, dysplasia of the biliary epithelium, and eventually CCC. These studies also suggested that the LSC compartment is the most likely candidate for oncogenic events[115,116,119-122]. Nevertheless, these newly published studies raise one question: how can one pathway, Notch signaling, contribute to two different subtypes of PLC: HCC and CCC? Of note, the balance between Notch/Wnt signaling has been proposed to be crucial for the determination of the LSC cell fate in liver disease. Activation of Notch signaling in LSCs leads to biliary specification; in contrast, Wnt signaling activation inhibits default-activated Notch signaling via Numb (a target of

canonical Wnt signaling), allowing LSCs to escape the biliary cell fate and acquire a hepatocellular specification[123-125]. Therefore, based on previous studies and to the best of our knowledge[123-126], we propose that the balance between Notch/Wnt signaling pathways determines the oncogenic transformation of LSCs into HCC, CCC, or cHCC-CC phenotype. The predominance of Notch over the Wnt signaling in LSCs leads to the CCC phenotype, and activation of Wnt signaling likely prevents activation of the Notch pathway and thus leads to the HCC phenotype. When the comparison is balanced between the two signaling pathways, the cell has a higher probability of entering the cHCC-CC phenotype. In summary, the role of such a pleiotropic pathway in liver regeneration

and liver diseases seems to be highly context dependent. Additional research is required to clearly establish the effects of the Notch signaling pathway during hepatocarcinogenesis. Hedgehog signaling pathway The Hedgehog signaling pathway is one of the key regulators of embryonic development. Mammals have three Hedgehog Anacetrapib homologues, Sonic (SHH), Indian (IHH), and Desert (DHH), of which Sonic is the best studied. Like the Wnt and Notch pathways, the Hedgehog signaling pathway also plays significant roles in stem cell self-renewal[127] and cancer cell proliferation[128,129]. Sicklick et al[130] showed that Hedgehog signaling is conserved in hepatic progenitors from fetal development through adulthood and is essential for the maintenance of LSC survival.