title: Novel feedback inhibition of surface antigen synthesis by mammalian target of rapamycin (mTOR) signal and its implication for hepatitis B virus tumorigenesis and therapy.
abstract: Ground glass hepatocytes (GGHs) harboring hepatitis B virus (HBV) pre-S mutants have been recognized as precursor lesions of hepatocellular carcinoma (HCC). Previously, we observed the activation of mammalian target of rapamycin (mTOR) in GGHs and HCCs, together with a decreased expression of HBV surface antigen (HBsAg) in HCC tissues. It is, therefore, hypothesized that the activation of mTOR during HBV tumorigenesis may potentially down-regulate HBsAg expression. In this study, we verified an inverse relationship between the expression of HBsAg and phosphorylated mTOR (p-mTOR) in 13 of 20 paired nontumorous liver and HCC tissues. In vitro, wild-type or mutant pre-S proteins could activate mTOR in the HuH-7 cell line. Interestingly, the up-regulated mTOR, in turn, suppressed HBsAg synthesis at the transcriptional level via the transcription factor, Yin Yang 1 (YY1), which bound to nucleotide 2812-2816 of the pre-S1 promoter. This inhibitory effect by the mTOR signal could be abolished by the knockdown of histone deacetylase 1 (HDAC1). 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.
  
  
  CONCLUSIONS
  The activation of mTOR signal in GGHs may feedback suppress HBsAg synthesis during HBV tumorigenesis and explain the observed decrease or absence of HBsAg in HCC tissues. Therapy using mTOR inhibitors for HCCs may potentially activate HBV replication in patients with chronic HBV infection.
authors: Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan.
authors: Chiao-Fang
authors: CF
authors: Teng
authors: Han-Chieh
authors: HC
authors: Wu
authors: Hung-Wen
authors: HW
authors: Tsai
authors: Her-Shyong
authors: HS
authors: Shiah
authors: Wenya
authors: W
authors: Huang
authors: Ih-Jen
authors: IJ
authors: Su
mesh_terms: D000943:Antigens, Differentiation / Q000235:genetics*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002478:Cells, Cultured; D025461:Feedback, Physiological; D015967:Gene Expression Regulation, Viral; D006514:Hepatitis B Surface Antigens / Q000096:biosynthesis* / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000943:Antigens, Differentiation; D006514:Hepatitis B Surface Antigens; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases