癌化是一個多步驟的過程，這其中又和致癌基因的活化與腫瘤抑制基因的失去活性有關。除此之外，而鼻咽癌的發生也被認為與遺傳、環境因子以及 EB 病毒的感染有所關聯，近期在細胞的分子階層的研究也提供了一些與腫瘤生長或是抑制的了解。而近年來對鼻咽癌與正常鼻腔上皮細胞間特異性的基因表現亦有較系統性的研究。在此，我們利用differential display 的方法來找出與控制正常鼻腔上皮細胞生長或是與鼻咽癌發生有關的基因。我們以 Ltk3 和T11CA為引子（primer）並且找到了一個約有379個鹼基對（base pair）的cDNA片段，而以北方墨點法（northern hybridization）證明此片段只在正常鼻腔上皮細胞中表現，但是並不會在三株鼻咽癌細胞株（HONE-1，NPC-TW01，NPC-TW04）中測得；進一步分析其DNA序列發現鹼基對1至230與EST database中的一段序列相似（Id：1308378），而231至379則為Alu-like的序列。
我們也利用了不同的引子組合來進行differential display並在鼻咽癌細胞株中發現了一個長約130個鹼基對cDNA片段，而序列分析結果顯示其與甲狀腺激素受體α2（TR-α2/c-erbA-α2）有很高的相似性。當以此130個鹼基對的cDNA片段或是以一個TR-α2的cDNA序列內部分特異性高的轉譯區域（coding region）為探針（probe），並且進行北方墨點法分析，均可在鼻咽癌細胞株中測得一約2.7kb的RNA表現，但是並不會在正常鼻腔上皮細胞中得到此結果。而再進一步以RNA原位雜交法（in situ hybridization）分析來自鼻咽癌病患及對照組的臨床檢體，我們發現在24個為正常鼻咽部上皮細胞的臨床檢體中，僅有一個呈陽性反應（4.2%）；而在27個初期腫瘤的檢體中，則有5個呈陽性反應（18.5%）﹔此外，在24個復發的腫瘤檢體中，則有高達15個呈陽性反應（62.5%）。因此，TR-α2在復發的鼻咽癌臨床檢體中的陽性率高於在正常鼻咽部上皮細胞中，而且具有統計上的意義（P<0.00001）。
而關於TR-α2的大量表現與鼻咽癌的關聯性，則是認為TR-α2具有抑制甲狀腺激素-甲狀腺激素受體（TR-α1，β1及β2）活性的功能，進而影響到甲狀腺激素受體（TR-α1，β1及β2）傳遞來自甲狀腺激素的訊息，而這些訊息又和細胞的增生（proliferation），代謝（metabolism）及凋亡（apoptosis）過程有關。因此，甲狀腺素受體α1，β1及β2被認為具有控制細胞生長的功能，而α2則是具有dominant negative的活性。為了進一步釐清甲狀腺激素受體在鼻咽癌細胞生長過程中所扮演的角色，我們構築了一個具有誘導TR-α1大量表現的鼻咽癌細胞株，並且分析TR-α1對鼻咽癌細胞株的影響。我們發現，當TR-α1被誘導表現後，能夠減緩鼻咽癌細胞珠的生長速率以及降低腫瘤細胞株在洋菜膠上的生長能力﹔同時，在以裸鼠為腫瘤生長分析的動物模型中，被誘導表現出TR-α1的鼻咽癌細胞株明顯的降低其在裸鼠上的腫瘤生長能力。因此，我們推論TR-α1對鼻咽癌細胞的生長具有抑制的效果。然而，也有可能是因為被誘導而大量表現的TR-α1改變了甲狀腺激素受體間的平衡，進而影響了細胞的生長情況。

Carcinogenesis is a multiple step process involving the activation of oncogenes and loss of function of tumor suppressor genes. The aetiology of nasopharyngeal carcinoma (NPC) is coincided with genetic factors, environmental factors and Epstein-Barr virus infection. Molecular investigation of cellular markers offered a lot of information about tumor growth promotion or suppression activity. However, systemic study has to be performed to identify genes specifically expressed between normal nasal epithelial cells and NPC cells. Thus, in our study, differential display was used to identify genes involving in normal nasal epithelial cells growth control or tumorigenesis of NPC. Using Ltk3 and T11CA as primers, a 379bps cDNA fragment (CN3) was obtained. A 3.5kb mRNA was detected in normal nasal epithelial cells but not in NPC cell lines, HONE-1, NPC-TW01, NPC-TW04 cells. Blast search of the CN3 cDNA sequences revealed that it contained a sequence homologue with EST database（Id: 1308378）from nts. 1 to 230 and Alu-sequences from nts. 231 to 379.
Using different primers combination, we identified another 130bps cDNA fragment showing homology with thyroid hormone receptor α2 (TR-α2 or c-erbA-α2) in NPC cell lines. Northern blot analysis using the 130bps cDNA fragment and a TR-α2 specific cDNA containing part of the coding region as probes, we were able to detect a 2.7kb transcript in NPC cell lines but not in normal nasal epithelial cells. RNA in situ hybridization was used to detect TR-α2 expression in clinical biopsies from NPC patients and non-tumor control. TR-α2 mRNA was detected in 1 out of 24 (4.2%) normal nasopharynx epithelium biopsies, in 5 out of 27 (18.5%) primary and 15 out of 24 (62.5%) recurrent tumors. The positive rate of TR-α2 expression in recurrent NPC biopsies was significantly higher than that in normal nasopharynx epithelium (P<0.00001).
Only three thyroid hormone receptor isoform α1, β1 and β2 bind thyroid hormone (TH) and are considered to be true TRs. TR-α2 unable to bind TH responsive element on DNA and has been shown to exert dominant negative action on TR-α1. TRαs regulate many important processes such as proliferation, differentiation and apoptosis. To find out whether TRαs played roles in growth control of NPC cells, we generated a TR-α1-inducible NPC cell line. Induced expression of TR-α1 in NPC cell line reduced cell proliferation and anchorage-independent growth activity in agar. Tumor formation ability in nude mice was also markedly reduced in NPC cells after treated with inducer in drinking water than those without TR-α1 expression or vector-transfectants control. Thus, our results postulated that TR-α1 function as a tumor suppressor in NPC tumorigenesis. However, induced overexpression of TRa1 might perturb the balance and contribute the role in growth control

Abstract-------------------------------------------------------------------------------------------1
中文摘要-----------------------------------------------------------------------------------------3
致謝-----------------------------------------------------------------------------------------------5
目錄-----------------------------------------------------------------------------------------------6
圖表目錄-----------------------------------------------------------------------------------------9
第一章 前言------------------------------------------------------------------------------------11
1. 鼻咽癌概論 (Overview of Nasopharyngeal Carcinoma)-----------------------12
1-1 鼻咽癌 (Nasopharyngeal carcinoma)---------------------------------------------12
1-2 鼻咽癌之病理分類與症狀 (Pathological classification and symptom)-----12
1-3 病原學 (Etiology)-------------------------------------------------------------------13
1-3-1環境因子 (Environmental factor)-------------------------------------------------13
1-3-2 EB病毒感染 (Epstein-Barr virus infection)-------------------------------------14
1-3-3遺傳因子 (Genetic factor)----------------------------------------------------------16
1-4 鼻咽癌在分子生物學上之研究
(Molecular biology investigation and NPC)------------------------------------17
2. 甲狀腺激素受體概論 (Overview of Thyroid Hormone Receptors (TRs))-20
2-1 甲狀腺激素受體的特徵（Characteristics of thyroid hormone receptors）-20
2-2 轉錄作用的調節（Transcriptional regulation of TRs）------------------------24
2-3 甲狀腺激素受體的變異與相關疾病---------------------------------------------27
（Disorders of TRs and related diseases）
第二章 材料及方法 (Material and Methods)---------------------------------------------30
試劑表---------------------------------------------------------------------------------31
2-1 細胞培養（Cell culture）-----------------------------------------------------------35
2-2 Differential display (DD-PCR)-----------------------------------------------------35
　2-3 勝任細胞之製備（Competent cell preparation）--------------------------------36
2-4 DNA轉形（DNA transformation）-----------------------------------------------37
2-5 小量質體製備法（Mini-scale plasmid preparation）---------------------------37
2-6 大量質體製備法（Large--scale plasmid preparation）-------------------------37
2-7 DNA定序（DNA sequencing）---------------------------------------------------38
2-8 DNA 探針之製備（DNA probe preparation）----------------------------------39
2-9 北方墨點法（Northern hybridization）-------------------------------------------39
2-10 南方墨點法（Southern hybridization）-------------------------------------------40
2-11 pTRα2C/SK質體之構築與cRNA探針之製備（Plasmid construction and cRNA probe preparation）---------------------------------------------------------40
2-12 臨床檢體（Specimens）------------------------------------------------------------40
2-13 RNA原位雜交法（RNA in situ hybridization）-------------------------------41
2-14 質體構築（Plasmid construction）-------------------------------------------------42
2-15 Tet-on誘導性鼻咽癌細胞株之建立-----------------------------------------------42
（Tet-on iducible cell lines construction）
2-16 免疫沉澱法（Immunoprecipitation）---------------------------------------------43
2-17 細胞增生實驗（Cell proliferation）-----------------------------------------------43
2-18 細胞獨立停泊實驗（Anchorage-independent growth）------------------------43
2-19 腫瘤生長實驗（Tumorigenicity in nude mice）---------------------------------44
第三章 研究目的I (Aim I)-------------------------------------------------------------------45
第四章 結果 I (Results I)--------------------------------------------------------------------46
4-1 在正常鼻腔上皮細胞而不在鼻咽癌細胞株中測得CN3 cDNA片段------48
CN3 obtained from normal nasal epithelial cells but not in NPC cell line-
4-2 定序以及利用北方墨點法證明---------------------------------------------------49
Sequencing and confirmation with northern hybridization
4-3 TR-α2基因在鼻咽癌細胞株中而非正常上皮細胞的獨特表現-----------49
TR-α2 gene is exclusively expressed in NPC cell lines but not in normal nasal epithelial cells
4-4 TR-α基因並未發生放大或重組現象--------------------------------------------50
No amplification or rearrangement exists in genomic DNA of TR-α
4-5 以RNA原位雜交法分析TR-α2的表現---------------------------------------51
RNA in situ hybridization of TR-α2
第五章 討論I（Discussion I）--------------------------------------------------------------53
第六章 研究目的 II (Aim II)----------------------------------------------------------------60
第七章 結果 II (Results II)------------------------------------------------------------------62
7-1 Tet誘導表現系統--------------------------------------------------------------------63
Tet-inducible sysyem
7-2 TRα1基因在鼻咽癌細胞株中的誘導表現-------------------------------------64
Inducible expression of TRα1 gene in NPC cell line
7-3 過量表現之TR-α1抑制NPC-TW04細胞的增生及獨立停泊生長能力--64
Overexpression of TR-α1 inhibited the cell proliferation
and anchorage-independent growth ability of NPC-TW04
7-4 TR-α1的表現抑制NPC-TW04細胞在裸鼠上的生長-----------------------65
TR-α1 expression inhibited the growth of NPC-TW04 cells
injected in nude mice
第八章 討論 II (Discussion II)--------------------------------------------------------------67
第九章 參考文獻 (References)-------------------------------------------------------------71
圖表（Figures and Tables）----------------------------------------------------------------98
附錄 (Appendix)-----------------------------------------------------------------------------123
圖表目錄
Table 1. American Joint Committee on Cancer Nasopharynx
Cancer Staging System-------------------------------------------------------------99
Table 2. Laboratory Tests for EBV---------------------------------------------------------100
Table 3. EBV-Associated Diseases---------------------------------------------------------101
Table 4. Clinical data and in situ hybridization results of TR-α2
in patients with NPC---------------------------------------------------------------102
Tabel 5. Tumorigenicity of NPC-TW 04 transfectants-----------------------------------103
Figure 1. Schemaic diagram of thyroid hormone receptor proteins.-------------------104
Figure 2. Domain structure of the TR molecule.------------------------------------------105
Figure 3. Model of gene repression by unliganded TR and
activation by liganded TR.-------------------------------------------------------106
Figure 4. The map of 3’ -unique region（nts1410-2015）of
TRα2 recombinant plasmid-----------------------------------------------------107
Figure 5. TRα1 tet-on inducible plasmid construction flowchart.--------------------108
Figure 6. Scheme of gene regulation in the Tet-On system.-----------------------------109
Figure 7. The differential display technique-----------------------------------------------110
Figure 8. Differential display of genes expressed in normal nasal cavity
epithelial cells and NPC cells.---------------------------------------------------111
Figure 9. Northern blot analysis of RNAs from normal nasal epithelial
cells and HONE-1 cells.----------------------------------------------------------112
Figure 10. Sequences of CN3 cDNA fragment.-------------------------------------------113
Figure 11. Northern blot of total RNAs from normal nasal epithelial cells
and various NPC cell lines.---------------------------------------------------114
Figure 12. Band pattern and sequence alignment of T11CAP2NPC1-8
cDNA fragment with c-erb A-α2----------------------------------------------115
Figure 13.Northern profiles of c-erb A-α2 (TR-α2) gene specifically
expressed in NPC cell lines.-----------------------------------------------------116
Figure 14. Southern blot analysis revealing similar TR-α genomic
organization between HONE-1 and LCL cell lines.--------------------------117
Figure 15. RNA in situ hybridization showing c-erb A-α2 (TR-α2)
expression in NPC but in normal nasopahrynx epithelium.-----------------118
Figure 16. Northern blot analysis and immunoprecipitation
showing doxycycline- regulatable expression of TRa1 gene.--------------119
Figure 17. TRa1 inhibited the growth and soft-agarose cloning
efficiency of NPC-TW 04 cells.-------------------------------------------------120
Figure 18. Tumorigenicity of NPC-TW 04-06-S14 and
NPC-TW 04-06-V cells.----------------------------------------------------------121

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