臺灣博碩士論文加值系統

肝癌 (Hepatocellular carcinoma, HCC)是世界上引起人類死亡的重要癌症之一，而慢性B型肝炎病毒 (hepatitis B virus, HBV)感染已知為其主要的致病因子之一。慢性B型肝炎病毒感染的毛玻璃肝細胞 (ground glass hepatocytes, GGHs)的內質網 (endoplasmic reticulum, ER)中已被證實含有B型肝炎病毒的pre-S突變蛋白，會造成內質網壓力、DNA損害，並具有誘發導致結節性增生及細胞轉形的能力。毛玻璃肝細胞因此被視為肝癌發生的前兆病變。過去，我們實驗室在毛玻璃肝細胞與肝癌組織中觀察到哺乳動物雷帕黴素標靶蛋白 (mammalian target of rapamycin, mTOR)信息的活化，以及B型肝炎病毒表面抗原 (HBV surface antigen, HBsAg)在肝癌中的減少表現。因此，我們假設哺乳動物雷帕黴素標靶蛋白信息在肝癌演變過程中的活化，可能潛在地抑制B型肝炎病毒表面抗原的表現。在本研究中，我們首先利用西方點墨法偵測B型肝炎病毒表面抗原與磷酸化的哺乳動物雷帕黴素標靶蛋白在20個人類肝組織對中的表現量，並在13個肝組織對中觀察到兩者在非腫瘤與腫瘤組織的表現量呈現相反的關係。在HuH-7肝細胞株中的研究顯示，野生型與突變型的pre-S蛋白的表現會活化哺乳動物雷帕黴素標靶蛋白。有趣的是，活化的哺乳動物雷帕黴素標靶蛋白信息會進一步地調控結合在pre-S1啟動子的核甘酸區域2812至2816位置上的陰陽蛋白1 (Yin Yang 1, YY1)轉錄因子，而在轉錄層面抑制B型肝炎病毒表面抗原的表現。利用組蛋白去乙醯酶 (histone deacetylase, HDAC)抑制劑SAHA與核醣核酸干擾技術，我們發現組蛋白去乙醯酶1參與在此負向調控中。在免疫共沉澱分析的實驗中我們觀察到，組蛋白去乙醯酶1會在哺乳動物雷帕黴素標靶蛋白活化之下與陰陽蛋白1轉錄因子相結合。進一步研究顯示，陰陽蛋白1與組蛋白去乙醯酶1之間的結合可能與陰陽蛋白1受到哺乳動物雷帕黴素標靶蛋白信息的乙醯化修飾有關。綜合上述結果，pre-S蛋白所活化的哺乳動物雷帕黴素標靶蛋白信息可能誘發陰陽蛋白1與組蛋白去乙醯酶1轉錄複合體的形成而結合並回饋抑制pre-S1啟動子的轉錄活性。毛玻璃肝細胞中哺乳動物雷帕黴素標靶蛋白信息的活化可能在肝癌演變過程中回饋抑制B型肝炎病毒表面抗原的表現。此研究第一次提出一個新穎的分子機制以解釋我們在肝癌組織中所觀察到的B型肝炎病毒表面抗原的減少表現，且在肝癌的臨床病理與治療上具有重要的意義。在臨床病理上，我們的研究結果暗示，B型肝炎病毒表面蛋白在病人血清或肝癌組織中的減少表現並不一定是個好的現象，對特定病人而言，反而可能代表著哺乳動物雷帕黴素標靶蛋白信息的活化而疾病正逐步演變為肝癌的徵兆。此外，利用哺乳動物雷帕黴素標靶蛋白抑制劑對慢性B型肝炎病毒感染的肝癌病患進行標靶治療，可能潛在地造成B型肝炎病毒表面抗原的表現與B型肝炎病毒的複製，進而導致不好的病徵。此研究結果突顯出，以哺乳動物雷帕黴素標靶蛋白做為標靶治療B型肝炎病毒相關的肝癌病患時，利用抗病毒藥物搭配哺乳動物雷帕黴素
標靶蛋白抑制劑共同治療的必要性。

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.

Contents ------------------------------------------------ 1
Abbreviations ------------------------------------------- 5
Introduction -------------------------------------------- 8
1. Epidemiology and virologic characteristics of
hepatitis B virus (HBV) ---------------------------- 8
1.1. Epidemiology of HBV --------------------------- 8
1.2. Virologic characteristics of HBV -------------- 8
1.2.1. Structure and genome organization of HBV ---- 9
1.2.2. Replication of HBV genome ------------------- 9
1.2.3. Acute HBV infection ------------------------ 10
1.2.4. Chronic HBV infection -----------------------10
2. Pathogenesis of HBV-related hepatocellular carcinaoma
(HCC) --------------------------------------------- 11
2.1. Insertional mutagenesis of HBV genome -------- 12
2.2. Transactivating functions of HBx protein ----- 13
2.3. Ground glass hepatocytes (GGHs) contain pre-S
deletion mutants and exhibit ER stress,
representing preneoplastic lesions of HCC ---- 14
2.4. Pre-S deletion mutants represent new HBV viral
oncoproteins --------------------------------- 15
2.4.1. Both pre-S mutants induce ER stress signals and
oxidative DNA damage ----------------------- 15
2.4.2. Pre-S2 mutant additionally induces ER stress-
independent signals ------------------------ 16
2.4.3. Transgenic mice of pre-S2 mutants develop
dysplastic changes and HCC ----------------- 17
2.4.4. Pre-S deletions provide a new risk marker for
the development of HCC --------------------- 17
2.5. mTOR signaling plays important roles in pre-S
mutants-induced tumorigenesis ---------------- 17
3. Structure and functions of mammalian target of
rapamycin (mTOR) ---------------------------------- 19
3.1. Domain structure of mTOR --------------------- 19
3.2. Molecular composition of mTOR complexes ------ 20
3.3. Substrates and actions of mTOR complexes ----- 21
3.3.1. mTORC1 regulates S6K1 and 4E-BP1 ----------- 21
3.3.2. mTORC1 regulates YY1 ----------------------- 21
3.3.3. mTORC1 regulates STAT3 --------------------- 22
3.3.4. mTORC1 regulates HIF-1 ------------------- 22
3.3.5. mTORC1 regulates ATG13 and ULK1 ------------ 23
3.3.6. mTORC1 and mTORC2 regulate SGK1 ------------ 23
3.3.7. Substrates and actions of mTORC2 ----------- 24
3.4. Upstream regulators of mTOR complexes -------- 24
3.4.1. Nutrients regulate mTORC1 ------------------ 24
3.4.2. Growth factors regulate mTORC1 ------------- 25
3.4.3. Energy and stress regulate mTORC1 ---------- 26
3.4.4. Upstream regulation of mTORC2 -------------- 26
3.5. Roles of mTOR in the regulation of cellular
processes ------------------------------------ 27
3.5.1. mTOR in protein synthesis ------------------ 27
3.5.2. mTOR in metabolism ------------------------- 28
3.5.3. mTOR in cancer ----------------------------- 29
3.5.4. mTOR in ageing ----------------------------- 30
3.6. Roles of mTOR in the regulation of HBV
replication ---------------------------------- 30
Rationale and Hypothesis ------------------------------- 32
Specific Aims and Experimental Designs ----------------- 33
1. To evaluate the feedback inhibition of LHBs expression
by mTOR activation -------------------------------- 33
1.1. To study the clinical correlations between LHBs
expression and mTOR activation --------------- 33
1.2. To observe the changes in LHBs levels accompanied
by mTOR activation --------------------------- 33
1.3. To verify the effect of mTOR activation on LHBs
expression and secretion --------------------- 33
1.4. To examine the effect of mTOR activation on pre-
S1 promoter activity ------------------------- 33
2. To explore the molecular mechanism of LHBs suppression
by mTOR activation -------------------------------- 34
2.1. To determine the regulatory region of mTOR signal
on pre-S1 promoter --------------------------- 34
2.2. To identify the transcription factor (TF)
responsible for pre-S1 promoter regulation by
mTOR signal ---------------------------------- 34
2.3. To investigate the critical TF-mediated
transcriptional control of pre-S1 promoter --- 34
2.4. To study the expression profiles of downstream
signaling of mTOR ---------------------------- 34
Materials and Methods ---------------------------------- 35
1. Clinical specimen collection ---------------------- 35
2. Plasmid construction ------------------------------ 35
3. Cell line and transient transfection -------------- 35
4. Western blot analysis ----------------------------- 35
5. Reverse transcription-PCR (RT-PCR) ---------------- 36
6. Real-time PCR ------------------------------------- 36
7. Luciferase reporter assay ------------------------- 36
8. Extraction of cytoplasmic and nuclear proteins ---- 37
9. Electrophoretic mobility shift assay (EMSA) ------- 37
10. DNA affinity precipitation assay (DAPA) ---------- 37
11. Co-immunoprecipitation (Co-IP) studies ----------- 38
12. cDNA microarray analysis ------------------------- 38
13. Statistical analysis ----------------------------- 38
Results ------------------------------------------------ 39
1. Decreased LHBs expression was correlated with
increased mTOR activation in paired
non-tumorous liver and HCC tissues ---------------- 39
2. Expression of LHBs was stepwise decreased with
concurrent mTOR activation over time in HuH-7 cells --
---------------------------------------------------- 39
3. Inhibition of mTOR restored LHBs expression at both
RNA and protein levels ---------------------------- 40
4. Activation of mTOR suppressed both expression and
secretion of LHBs --------------------------------- 40
5. Activation of mTOR repressed pre-S1 promoter
activity ------------------------------------------ 40
6. Nucleotide 2812 to 2816 of pre-S1 promoter was the
candidate region responsible for LHBs suppression by
mTOR signal --------------------------------------- 41
7. YY1 bound to the nucleotide 2812-2816 site of pre-S1
promoter in vitro --------------------------------- 42
8. Activation of mTOR enhanced YY1 expression and nuclear
localization -------------------------------------- 42
9. Recruitment of HDAC1 by YY1 mediated pre-S1 promoter
repression by mTOR signal ------------------------- 43
10. Association between YY1 and HDAC1 by mTOR signal
seems not to be mediated by a bridging factor,
suggesting other regulators involved in the
regulation --------------------------------------- 44
11. Acetylation levels of YY1 and HDAC1 were modulated by
mTOR signal, implying a possible role of post-
translational acetylation modifications in the YY1-
HDAC1 association -------------------------------- 44
12. S6K1 and 4E-BP1 showed consistently phosphorylated
patterns with mTOR and represented potential
downstream effector molecules of mTOR in HBV-related
HCC liver tissues -------------------------------- 45
13. Phosphorylated mTOR and 4E-BP1 expressions were
positively correlated with YY1 expression in HBV-
related HCC liver tissues ------------------------ 46
Discussions -------------------------------------------- 47
1. Decreased expression of HBsAg in serum or hepatocytes
represents an additional hallmark for mTOR signal
activation and HBV-related HCC tumorigenesis ------ 47
2. YY1-mediated transcriptional repression of pre-S1
promoter may be dependent on the up-regulation of YY1
expression levels by mTOR activation -------------- 48
3. Regulation of the YY1-HDAC1 association by mTOR signal
may be through modulation of the post-translational
acetylation modifications of YY1 ------------------ 49
4. Inhibition of HBsAg expression by mTOR signal was
implicated in the regulation of HBV replication --- 51
References --------------------------------------------- 52
Tables and Figures ------------------------------------- 72
Table 1. Primer sequences for shRNA oligonucleotides - 72
Table 2. Primer sequences for PCR of pre-S1 promoter
regions ------------------------------------- 73
Table 3. Primer sequences for site-directed mutagenesis -
---------------------------------------------- 74
Table 4. Primer sequences for RT-PCR and real-time PCR
assays -------------------------------------- 75
Figure 1. The inverse expression of LHBs and p-mTOR in
human liver tissues ------------------------ 76
Figure 2. Decreased expression of LHBs accompanied by
mTOR activation in hepatocytes ------------- 77
Figure 3. Restoration of both RNA and protein expressions
of LHBs by mTOR inhibition ----------------- 79
Figure 4. Suppression of both expression and secretion of
LHBs by mTOR activation -------------------- 83
Figure 5. Transcriptional inhibition of the pre-S1
promoter by mTOR activation ---------------- 84
Figure 6. Nucleotide 2812 to 2816 site of pre-S1 promoter
mediated transcriptional inhibition by
mTOR signal -------------------------------- 86
Figure 7. YY1 bound to the nucleotide 2812-2816 site of
pre-S1 promoter in vitro ------------------- 87
Figure 8. Up-regulation of YY1 expression and nuclear
localization by mTOR activation ------------ 88
Figure 9. HDAC1 recruitment by YY1 was required for mTOR
activation-induced pre-S1 promoter inhibition - --------------------------------------------- 90
Figure 10. Candidate bridging factors regulated by mTOR
signal linking YY1 to HDAC1 --------------- 94
Figure 11. Modulation of YY1 and HDAC1 acetylation by
mTOR signal ------------------------------- 96
Figure 12. Expression profiles of p-mTOR, p-S6K1 and p-4E-
BP1 in paired HBV-related HCC liver tissues --
-------------------------------------------- 97
Figure 13. Positive correlation among the expressions of
mTOR, p-4E-BP1, and YY1 in paired HBV-related
HCC liver tissues ------------------------- 98
Figure 14. Schematic depiction for the negative feedback
regulation of LHBs expression by mTOR signal - -------------------------------------------- 99
Figure 15. Hypothetic model for the recruitment of HDAC1
by YY1 to pre-S1 promoter by mTOR signal - 100
Appendix 1. Genome structure, surface gene organization,
and replication cycle of HBV ------------ 101
Appendix 2. Serology, virology, and chronologic
pathogenesis of HBV infection ----------- 102
Appendix 3. Expression patterns of HBsAg in GGHs and the
potential signals induced by pre-S mutants -- ------------------------------------------ 103
Appendix 4. Molecular composition and the signaling
pathway of mTOR ------------------------- 104
Appendix 5. Stepwise decreased expression of HBsAg from
GGHs to dysplastic hepatocytes and HCC in
HBV-related human livers ---------------- 105
Appendix 6. Summary of the regulation of YY1 by
acetylation and deacetylation ----------- 106

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