Conclusion: ZNF191 can directly bind to the CTNNB1 promoter and activate the see more expression of β-catenin and its downstream target genes such as cyclin D1 in hepatoma cell lines. This study uncovers a new molecular mechanism of transcription regulation of the β-catenin gene in HCC. (HEPATOLOGY 2012;55:1830–1839) Hepatocellular carcinoma (HCC) is a primary cancer of the liver and the fifth most common cancer worldwide, which is predominant in developing countries, with nearly 600,000 deaths each year worldwide.1 Various risk factors have been associated with HCC, including infection with hepatitis B virus and/or hepatitis C virus,2 aflatoxin B intake,3 heavy alcohol intake,4 hemochromatosis.5

The pathogenesis of the development and progression of HCC is far from being clear presently, and several cellular signal transduction Lenvatinib manufacturer pathways are involved in HCC, such as wingless-type (Wnt)/β-catenin, p53, pRb, mitogen-activated protein kinase (MAPK), Ras pathway.6 Of these pathways

activated in HCC, the canonical Wnt pathway is one of most frequently reported.1 In canonical Wnt signaling pathway, β-catenin is the central player. Under unstimulated conditions, β-catenin is phosphorylated by interactions with glycogen synthase kinase 3β (GSK-3β), and forms a destruction complex with axin and the adenomatous polyposis coli protein (APC).7, 8 Mutations in the N-terminal region of β-catenin can prevent its phosphorylation and subsequent degradation, and this stabilizes the protein and the mutant protein accumulates in the nucleus, and causes an elevated level of constitutive transcriptional activation by β-catenin/TCF complexes, which contributes to liver carcinogenesis.9 In HCC aberrant activation of the canonical Wnt//β-catenin signaling pathway includes mutations in β-catenin, Axin1, Axin2, or APC genes.10-12 However, some studies have revealed that 35%-80% of HCCs with β-catenin nuclear and cytoplasmic accumulation is not associated with these gene mutations. This phenomenon implies that the pathway may be activated by some other mechanisms.9, 13, 14 β-Catenin accumulation Inositol monophosphatase 1 leads to activation of target genes, such

as cyclin D1, c-Myc, implicated in human cancer.15-17 In addition to numerous studies that focused on β-catenin protein stabilization and subcellular localization, some studies reported that β-catenin messenger RNA (mRNA) levels were elevated in human cancers including HCC.16, 18 This suggests that transcription deregulation of the β-catenin gene itself may be an important factor during tumor development. However, only several transcription factors have been identified with high-affinity binding to the CTNNB1 promoter, such as AP1, LEF/TCF, NKX2-5, TRβ,16, 19, 20 which have been reported to be involved in some physiological and pathophysiological processes. However, the mechanism of transcription regulation of β-catenin gene in HCC remains unknown.