In addition, our finding that the hiPSC-derived hepatocytes are competent to respond to hepatoselective pharmaceuticals implies that patient-specific iPSC-derived hepatocytes will facilitate the identification of drugs that can treat inborn errors of liver metabolism. We thank Paula North for analyses of teratomas, Tom Wagner for technical support, and Brian Link for advice with confocal analyses. Additional Supporting Information may be found in the online version of this Selleckchem Caspase inhibitor article. “
“One of the serious sequelae of chronic hepatitis B virus (HBV) infection is hepatocellular carcinoma (HCC). Among all the proteins encoded by the HBV genome, hepatitis B virus X protein (HBx)

is highly associated with the development of HCC. Although Notch1 signaling has been found to exert a tumor-suppressive function during HCC development, the mechanism of interaction between HBx expression and Notch1 signaling needs to be explored. In this study, we report that HBx expression in hepatic and hepatoma cells resulted in decreased endogenous protein levels of Notch1 intracellular domain (ICN1) and messenger RNA levels of its downstream target genes. These effects Wee1 inhibitor were due to a reduction of Notch1 cleavage by HBx through the suppression

of presenilin1 (Psen1) transcription rather than inhibition of Notch1 transcription or its ligands’ expression. MCE Through transient HBx expression, decreased ICN1 resulted in enhanced cell proliferation, induced G1-S cell cycle progression, and blunted cellular senescence in vitro. Furthermore, the effect of blunted senescence-like growth arrest by stable HBx expression through suppression of ICN1 was shown in a nude mouse xenograft transplantation model. The correlation of inhibited Psen1-dependent Notch1 signaling and blunted senescence-like growth arrest was also observed in HBV-associated HCC patient tumor samples. Conclusion: Our results reveal a novel function of HBx in blunting

senescence-like growth arrest by decreasing Notch1 signaling, which could be a putative molecular mechanism mediating HBV-associated hepatocarcinogenesis. (HEPATOLOGY 2010;) Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and the third leading cause of cancer-related death in humans, with nearly 600,000 deaths annually worldwide.1, 2 Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor for the development of HCC, especially in southeastern Asia and sub-Saharan Africa.3-5 Several processes are involved in the development of HBV-associated hepatocellular carcinoma, including integration of HBV genes into host cell genome, sustained cycles of necrosis-inflammation-regeneration, activation of oncogenic pathways, and inactivation of tumor-suppressive pathways by various viral proteins.