| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 100 === Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), one of the most important causes of cancer death in the world. Ground glass hepatocytes (GGHs) in chronic HBV infection contain HBV pre-S deletion mutants in endoplasmic reticulum (ER) and may induce ER stress and contribute to DNA damage, nodular proliferation, and transforming ability. GGHs hence have been recognized as precursor lesions of HCC. Previously, we observed the activation of mammalian target of rapamycin (mTOR) kinase 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 expressions of HBsAg and phosphorylated mTOR (p-mTOR) in 13 of 20 paired non-tumorous liver and HCC tissues. In vitro, the wild-type or mutant pre-S proteins could activate mTOR in HuH-7 cell line. Interestingly, the up-regulated mTOR signal in turn suppressed HBsAg synthesis and extracellular secretion at the transcriptional level via the transcription factor Yin Yang 1 (YY1) which bound to nucleotide 2812 to 2816 site of pre-S1 promoter, the endogenous promoter of HBV surface gene. This inhibitory effect by mTOR signal could be abolished by treatment of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) or knockdown of HDAC1 by RNA interference, suggesting an involvement of HDAC in the pre-S1 promoter inhibition. Furthermore, YY1 was found to be physically associated with HDAC1 in a manner dependent on mTOR activation. The association between YY1 and HDAC1 may be modulated by the acetylation modifications of YY1 by mTOR signal. Collectively, pre-S proteins-induced mTOR activation may recruit YY1-HDAC1 transcriptional complex onto the pre-S1 promoter to feedback suppress transcription from the pre-S1 promoter. The activation of mTOR signal in GGHs may feedback suppress HBsAg synthesis during the process of HBV tumorigenesis. This study for the first time proposes a novel molecular mechanism to explain the observed decrease or absence of HBsAg expression in HCC tissues and has important clinical and therapeutic implications. Clinically, the decreased level of HBsAg in serum or hepatocytes may not necessarily represent a good sign of disease improvement during the natural course of HCC development, but instead, it may potentially indicate the activation of mTOR and a disease progression toward tumorigenesis. Additionally, therapy using mTOR inhibitors for HCCs may potentially activate HBsAg expression and HBV replication and result in untoward clinical consequences, emphasizing the necessity of combining antiviral agents when mTOR inhibitors are used.
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