Furthermore, YY1 was physically associated with HDAC1 in a manner dependent on mTOR activation. Collectively, pre-S protein-induced mTOR activation may recruit the YY1-HDAC1 complex to feedback suppress transcription from the pre-S1 promoter. Conclusion: The activation of mTOR signal in GGHs may feedback suppress HBsAg synthesis during HBV tumorigenesis and explain the observed decrease or Copanlisib purchase absence of HBsAg in HCC tissues. Therapy using mTOR inhibitors for HCCs may potentially activate HBV replication in patients with chronic HBV infection. (HEPATOLOGY 2011 ) Chronic hepatitis B virus (HBV) infection has been recognized as a major risk factor for the development of hepatocellular carcinoma

(HCC).1 Several mechanisms have been proposed to explain HBV-related hepatocarcinogenesis, including insertional Selleck Caspase inhibitor mutagenesis of HBV genomes, inflammation, regeneration, and transactivating functions of HBV gene products, such as X protein and truncated middle surface protein.2, 3 Previously, we proposed HBV pre-S mutants as viral oncoproteins, which were accumulated in the endoplasmic reticulum (ER) of ground glass hepatocytes (GGHs).4 pre-S mutants can induce ER stress signals, oxidative

DNA damages, and transforming capabilities.5 GGHs are, therefore, recognized as the precursor lesions of HCCs.6 One intriguing observation in chronic HBV infection is the low detection rate of HBV surface antigen (HBsAg), usually below 20% of cases in HCC tissues, whereas HBsAg can be detected in almost 100% of cases in paired nontumorous livers.7 The same finding was observed in HBsAg-expressing transgenic mice, which were accompanied by a decreased or absent expression of HBsAg in HCCs.8 These observations indicate that the decreased HBsAg expression is a consistent phenomenon during the process of HBV tumorigenesis. Although the levels of HBV DNA and HBsAg usually decline along with the natural course of chronic HBV infection,9, 10 there exists such a possibility that host cell factors may become activated to inhibit HBsAg expression or HBV replication during

HBV tumorigenesis. This speculation gains support from one recent study reporting that the activation of mammalian target of rapamycin (mTOR)-signaling pathway inhibited the transcription of the HBV large surface antigen medchemexpress (LHBs) gene.11 Because mTOR is frequently activated in HCCs,12 the activated mTOR signal may account for the decreased expression of HBsAg in HCC tissues. Previously, we demonstrated that HBV pre-S mutants could activate the mTOR signal in GGHs.13 Therefore, there appears to an inverse relationship between the expression of HBsAg and the activation of mTOR during HBV tumorigenesis. The transcription of the LHBs gene is under control of the pre-S1 promoter.14 Several transcription factors may contribute to pre-S1 promoter activity, including TATA box-binding protein, hepatocyte nuclear factor 1 and 3, and Sp1.