Even though precise mechanisms on how NEFH regulates b-catenin are still needs to be further elucidated, epigenetic silencing of the NEFH gene in ESCC seems to be responsible for increased ��-catenin expression, leading to activation of ��-catenin/TCF-dependent transcription and key downstream effectors, leading to ESCC tumorigenesis. The nuclear localization of ��-catenin selleck kinase inhibitor is controlled by its phosphorylation state at NH2-terminal serine threonine residues regulated by Gsk3�� [62]. Phosphorylation of ��-catenin by Gsk3�� targets ��-catenin to ubiquitination and proteasome degradation. Thus, activation of the pathway represses ��-catenin degradation, resulting in nuclear accumulation of ��-catenin. In the nucleus, the ��-catenin-TCF/Lef complex activates target genes such as c-Myc and cyclin D1, which are involved in oncogenic transformation [4], [20]�C[26].
Previous studies have shown that
Chronic infection with hepatitis B virus (HBV) currently affects 350 million to 400 million people worldwide, and over 200,000 and 300,000 HBV-infected subjects die from decompensated hepatic cirrhosis (HC) and hepatocellular carcinoma (HCC), respectively, each year (1, 2). Chronic HBV infection results in approximately one-third of all HC cases and more than one-half of all HCC cases worldwide (3). The World Health Organization includes HBV in ��group 1�� human carcinogens (4). According to a sequence divergence of >8% in the entire genome, HBV has been classified into at least 8 genotypes so far.
HBV genotypes have distinct geographic distributions and have been shown to differ with regard to clinical liver diseases, outcomes, and responses to interferon treatment (5). In East Asia, where HBV genotypes B and C are endemic, viral factors of HBV, including genotype C infection, hepatitis B virus e antigen (HBeAg) expression, high viral load (>104 copies/ml), and mutations in the enhancer II/basal core promoter/precore (EnhII/BCP/PC) and the pre-S regions, as well as active hepatic inflammation contribute greatly to the development of advanced liver diseases, especially HCC (6�C16). Some of the mutations can happen years before a diagnosis of HCC is made and gradually accumulate during the progression of chronic liver diseases (9, 13�C16). Some of the mutations can promote the growth and aggressiveness of HCC cells and predict unfavorable prognoses of HCC patients after surgery (17�C19).
Thus, HBV mutations can predict the occurrence and prognosis of HCC in HBV-infected subjects. Chronic infection by HBV frequently AV-951 occurs in individuals infected perinatally (90%) or during childhood (20% to 30%), when the immune system is thought to be immature (2). About 8.5% of adult patients with acute hepatitis B in mainland China will develop a chronic infection, and those who develop a chronic infection are infected mostly with genotype C HBV (20).