The mice were withdrawn from Doxycycline (Dox) at 2 months old and subjected to 1) partial hepatectomy (PH) that primarily stimulates HC proliferation or 2) PH plus 2-AAFadministration that inhibits HC selleck kinase inhibitor proliferation and induces a LPC population. After 12 months, PH mice developed liver tumor in 15% (x/y) of the mice while PH+2-AAF mice developed more aggressive multinodular tumors in 60% (a/b) with lung

metastasis in 15%. Secondly, we have generated caTLR4 Tg mice using a-fetoprotein promoter (Afp-tTA: Tet(TRE)-caTIr4) to target LPCs. Dox was withdrawn either at the beginning of the last trimester of gestation (E14) or at 2 months after birth (P60). After 12 months, 58% (7/12) of the E14-withdrawaI mice developed liver tumors while only 9% (1/9) of P60-withdrawal mice had tumor, confirming the LPS/HB are the primary target of the TLR4 oncogenic pathway. Thirdly, we directly tested if expression of caTLR4 by a lentiviral vector induces Nanog in mature mouse HC, E12.5 HB, and PIL4 cells (p53 deficient HB cell line) in vitro. Nanog mRNA induction and colony formation in soft agar were detected in caTLR4-transduced HB and PIL4 cells but not in HC. These differential effects were associated with demethylation of a http://www.selleckchem.com/products/pirfenidone.html Nanog distal enhancer in HB compared to HC, particularly at an E2F1 binding site (nt −5113/-5106) shown to be critical for E2F1-NFĸB cooperation for optimal Nanog transcription.

Genome-wide NANOG-binding site analysis (ChlP-seq) in TICs demonstrates that NANOG regulates oxidative phosphorylation in mitochondria as a master regulator of mitochondria biogenesis. [Conclusion] These results support the notion that LPC/HB are the primary target of TLR4 oncogenic pathway because of epigenetic de-repression of Nanog involving DNA hypomethylation. Disclosures: Hidekazu Tsukamoto – Consulting: Shionogi & Co., S. P. Pharmaceutics; Grant/Research Support:

The Toray Co. The following people have nothing to disclose: Chia-Lin Chen, Jian-Chang Liu, Linda S. Sher, Lydia M. Petrovic, Keigo Machida Background: Transplantation of hepatic progenitor cells (HPCs) is considered to be promising alternative to organ transplantation for the MCE treatment of liver diseases. Understanding the role of redox status in HPCs is reguired for optimizing their expansion and differentiation. Nrf2 is a transcription factor that regulates cellular defenses against oxidative stress. Keap1 is the cytoplasmic binding partner of Nrf2, and suppression of Keap1 expression induces nuclear translocation of Nrf2 and expression of downstream antioxidant genes. Therefore, we investigated the role of the Keap1/Nrf2 signaling pathway in protecting HPCs from oxidative stress-induced cell death. Methods: We isolated Foxl1-expressing HPCs from FoxI1-Cre; RosaYFP/YFP mice and expanded clonal HPC cell lines in culture (1). We utilized lentiviral shRNAs to modulate expression of Keap1 and Nrf2 in HPCs.