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研究生:陳瑞楠
研究生(外文):Ruey-Nan Chen
論文名稱:探討肝癌細胞株中腦下垂體腫瘤轉型基因-1與Furin受甲狀腺素調控之分子機制
論文名稱(外文):Studying of regulation mechanism and physiological significance of PTTG1 and Furin by thyroid hormone
指導教授:林光輝林光輝引用關係
指導教授(外文):K. H. Lin
學位類別:博士
校院名稱:長庚大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
論文頁數:106
中文關鍵詞:甲狀腺素受體腦下垂體腫瘤轉型基因-1
外文關鍵詞:thyroid hormone receptorPTTG1furin
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甲狀腺激素(thyroid hormone)於體內有thyroxine、triiodothyronine與reverse-T3三種形式,於脊椎動物的生長、發育、分化及體內各種衡定的維持扮演重要角色,其生物活性主要透過與細胞核內甲狀腺素受體(thyroid hormone receptor;TR)結合至調控標基因之反應位元進而調控基因之轉錄活性而達成。據先前研究發現v-erbA 致癌基因能導致鳥類erythroleukemias及sarcomas之形成,另外,於眾多癌症中發現(包括肝癌)TR有突變及表現量發生改變之現象,此暗示了TR與癌症形成之關連關,但TR於該癌形成確切之角色及分子機制仍尚不明確。本研究已初步利用cDNA microarray篩選出受T3調控之基因,從中挑出與癌症相關之腦下垂體腫瘤轉型基因-1(Pituitary tumor-transforming gene 1,PTTG1)與Furin分別進行研究。研究結果發現PTTG1與Furin顯著受T3所調控,且兩調控機制於肝癌形成及癌細胞轉移中可能扮演重要之角色。PTTG1之研究結果顯示,此基因表現主要為受T3之負向調控Sp1所達成,而此調控機制可能於HCC之形成扮演一重要角色。而Furin之研究結果則發現,此基因受T3及TGF所正向調控,此調控具促進肝癌細胞之入侵能力。本研究顯示了PTTG1與Furin於肝癌細胞中之生理功能,而T3/TR於肝癌所扮演之角色仍尚待進一步釐清。
Thyroid hormone is a pleiotropic regulator of growth, differentiation and tissue homeostasis in higher organisms that acts through the control of target gene expression. Major T3 actions are mediated by specific high affinity nuclear receptors which are encoded by two genes, TRα and TRβ. Many studies reported on the relationship between circulating thyroid hormone levels, thyroid disease and human cancer. In 1986, a connection between TR and cancer became evident when the chicken TRα1 was characterized as the c-erbA proto-oncogene, the cellular counterpart of the retroviral v-erbA oncogene. v-erbA causes erythroleukemias and sarcomas in birds, and hepatocellular carcinomas in transgenic mice. Recently, many studies have analyzed the presence of quantitative or qualitative alterations in the expression of TR genes in different type of human neoplasias. While their role in liver tumor generation or progression is currently unclear.
This study characterized pituitary tumor transforming gene 1 (PTTG1) and furin previously identified in cDNA microarray screening for T3-responsive genes in HepG2-TRα1 cells. We elucidated the molecular mechanism of PTTG1 and furin regulation by T3 in isogenic HepG2 cell lines. The experimental results also revealed that T3-induced gene expression in human HCC cell lines resembles that observed in animal model studies. Furthermore, the clinicopathological significance of PTTG1 and furin expression in HCC were also investigated. The experimental results indicated that PTTG1 gene expression is mediated by Sp1 and is indirectly downregulated by T3. Additionally, T3 directly regulates furin gene expression, thereby enhancing its invasiveness. Nevertheless, the detailed role of TR during carcinogenesis requires further study.
Table of Content
指導教授推薦書
口試委員審定書
國家圖書館授權書………………………………………………….. iii
長庚大學授權書…………………………………………………….. iv
誌謝………………………………………………………………….. v
Abbreviations………………………………………………………… vi
摘要………………………………………………………………….. viii
Abstract………………………………………………………………. ix
Chapter One:Thyroid hormone receptors suppress pituitary tumor transforming gene 1 activity in hepatoma
1.1 Abstracts
1.1.1 Abstract in Chinese…………………………………………….. 1
1.1.2 Abstract in English……………………………………………... 2
1.2 Literature review
1.2.1 Introduction of Thyroid hormone receptors (TRs) and
thyroid hormone action…………………………………………
3
1.2.2 Thyroid hormone receptor in cancer…………………………… 5
1.2.3 TR and liver cancer…………………………………………….. 7
1.2.4 Introduction of biological functions of PTTG1………………… 7
1.2.5 Transformation ability of PTTG1……………………………… 8
1.2.6 Transactivation ability of PTTG1……………………………… 10

1.2.7 PTTG1 protein post-transcriptional modification -Phosphorylation of PTTG1………………………………………
11
1.2.8 PTTG1 binding factor………………………………………….. 12
1.2.9 Regulation mechanism of PTTG1 expression………..………… 12
1.3 Introduction……………………………………………………..... 14
1.4 Materials and methods
1.4.1 Cell culture……………………………………………………... 16
1.4.2 Immunoblot analysis…………………………………………… 16
1.4.3 Northern blot analysis………………………………………….. 16
1.4.4 Cloning the PTTG1 5’-flanking region and promoter
activity assay…………………………………………………...
17
1.4.5 Electrophoretic Mobility Shift Assay…………………………... 18
1.4.6 Experimental animals and human specimens………………….. 18
1.4.7 Recombinant adenovirus and infection………………………… 18
1.4.8 Establishing TRs/PTTG1/Sp1 knockdown stable HCC
cell lines………………………………………………………..
19
1.4.9 Detection of cell cycle phase by propidium iodide staining…… 20
1.4.10 Cell proliferation assay……………………………………….. 20
1.5 Experiment results
1.5.1 Effects of T3 on the PTTG1 mRNA and protein expression
in HepG2 cells………………………………………………....
21
1.5.2 Knockdown of TRs expression abolished repression
of PTTG1 by T3………………………………………………..
22
1.5.3 Effects of T3 and cycloheximide on the expression of PTTG1
mRNA……………………………………………………….....
22

1.5.4 Localization of a negative regulatory region in the PTTG1
promoter………………………………………………………..
23
1.5.5 T3-reduced Sp1 expression in HepG2-TRα1 cells…………….. 25
1.5.6 Overexpression of Sp1 activates PTTG1 promoter activity……. 25
1.5.7 T3 represses PTTG1 and Sp1 protein expression in vivo……… 27
1.5.8 Knockdown of Sp1 or PTTG1 expression inhibits HepG1-TRα1 cell growth………………………………………
28
1.5.9 Ectopic overexpression of PTTG1 promotes cell
proliferation in Hep3B hepatoma cells…………………………
29
1.6 Discussion 30

Chapter Two : Thyroid hormone promotes cell invasion through activation of furin expression in human hepatoma cell lines
2.1 Abstracts
2.1.1Abstract in Chinese……………………………………………. 45
2.1.2 Abstract in English……………………………………………. 46
2.2 Introduction 47
2.3 Materials and methods
2.3.1 Cell culture……………………………………………………. 49
2.3.2 Immunoblotting………………………………………………. 49
2.3.3 Northern blotting……………………………………………… 50
2.3.4 Effect of exogenous Smad on furin expression 50
2.3.5 Cloning the furin promoter fragments and assay of their
activities………………………………………………………
51
2.3.6 Electrophoretic mobility shift assay (EMSA)………………… 51

2.3.7 Animals……………………………………………………….. 51
2.3.8 Quantitative reverse transcription polymerase chain reaction
(Q-RT-PCR)..............................................................................
53
2.3.9 Zymography assay for MMP-2 and MMP-9…………………. 53
2.3.10 In vitro assay of invasive activity…………………………… 54
2.3.11 Human HCC specimens……………………………………... 54
2.3.12 Statistical analysis…………………………………………… 54
2.4 Experiment Results
2.4.1 Effects of T3 treatment on furin gene expression at both protein and mRNA levels…………………………………....
55
2.4.2 Stimulation of furin by TGF-β is mediated by the
Smad 3/4-dependent pathway………………………………...
57
2.4.3 Modulation of T3 and TGF-β pathways mediate activation
of furin expression by MAP kinases………………………….
58
2.4.4 In vivo expression of furin protein induced by T3..................... 59
2.4.5 T3 induces furin expression at the transcriptional level………. 60
2.4.6 Binding of TR to a -6328/-6288 fragment of the furin
promoter containing TREa……………………………………
61
2.4.7 Furin over-expression promotes cell invasion in vitro and
in vivo…………………………………………………………
62
2.4.8 Furin over-expression induced by T3 or TGF-β enhance
HepG2-TRα1 cell invasion in vivo……………………………
64
2.4.9 Furin is up-regulated in human HCC…………………………. 65
2.5 Discussion………………………………………………………... 66
Chapter Three : Summary 85

3.1 Systemically analyze protein profile targeted by Sp1
from cDNA microarray data…………………………………
85
3.2 The clinicopathologic significance of PTTG1/Sp1
expression in HCC……………………………………………
85
3.3 Characterize the functional roles of TRs in HCC…………… 86
Figures and Tables
Chapter one
Figure 1. T3 represses PTTG1 expression in HepG2 cell lines at
the protein level…………………………………………..
34
Figure 2. T3 represses PTTG1 expression in HepG2 cell lines at
the mRNA level…………………………………………..
35
Figure 3. Knockdown of TRs expression abolished repression
of PTTG1 by T3…………………………………………..
36
Figure 4. Cycloheximide (CHX) was ablated the response of
PTTG1 to T3-repression………………………………….
37
Figure 5. Regulation of PTTG1 expression by Sp1 at the
transcriptional level……………………………………….
38
Figure 6. Regulation of Sp1 family by T3 in HepG2-TR cells……... 39
Figure 7. Sp1 binds to PTTG1 promoter and enhances PTTG1 expression…………………………………………………
40
Figure 8. The PTTG1 was regulated by TR through Sp1 in both thyroidectomized rats and human HCC specimens………
42
Figure 9. Functional assay of PTTG1 in hepatoma cells…………… 43
Figure 10. Effect of PTTG1 on the cell cycle in the G0/G1 phase in various PTTG1 knockdown or overproducing cells……...
44

Chapter Two
Figure 1. Synergistic activation of furin by T3 and TGF-β in
HepG2 cell lines analyzed at the protein level………….
71
Figure 2. Induction of furin in three HCC cell lines expressing
endogenous TRs…………………………………………
72
Figure 3. Effects of T3 and TGF-β on the furin mRNA level in
HepG2 cell lines………………………………………...
73
Figure 4. Involvement of Smad3 and Smad4 in T3- and
TGF-β-induced furin expression………………………....
74
Figure 5. Modulation of T3 and TGF-β pathways mediate
activation of furin expression by MAP kinases…………..
75
Figure 6. Induction of furin expression by thyroid hormone in
rat liver……………………………………………………
76
Figure 7. T3-dependent activation of furin promoter by TR………... 77
Figure 8. Direct binding of TR proteins to the TRE spanning
-6328 to -6288 fragments of the furin gene promoter……
78
Figure 9. Overexpression of furin by thyroid hormone promotes
invasion of HepG2-TRα1 ………………………………..
79
Figure 10. Furin over-expression in HepG2 cells enhances tumor
invasion in SCID mice…………………………………..
80
Figure 11. Furin over-expression induced by T3 or TGF-β enhance
HepG2-TRα1 cell invasion in SCID mice………………
81
Figure 12. Over-expression of furin in human HCC……………….. 83
Figure 13. Co-operative model for T3-and TGF-β-activated furin
gene expression………………………………………….
84

Chapter Three
Table 1. Functional classification of Sp1-specific down stream
genes from cDNA microarray data……………………….
89
Table 2. Analysis of PTTG1, Sp1, Furin and TRs expression
level in specimens of HCC by Western blot………………
91
Table 3. Correlation among PTTG1, Sp1 and TRs in HCC……….. 91
Table 4. Correlation between Furin and TRs in HCC……………... 92
Publication list………………………………………………………. 93
References……………………............................................................ 94
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