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研究生：	薛祖欣 Hsueh, Tsu-Hsin
論文名稱：	HLA-C 基因座附近可能的鼻咽癌易感受基因的定位與特性分析 Identification and Characterization of Putative Nasopharyngeal Carcinoma-susceptible gene around Human Leukocyte Antigen C Locus
指導教授：	呂政展 Lu, Cheng-Chan 蔡森田 Tsai, Sen-Tien
學位類別：	碩士 Master
系所名稱：	醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2008
畢業學年度：	96
語文別：	英文
論文頁數：	131
中文關鍵詞：	單一核甘酸多型性、鼻咽癌、易感受基因
外文關鍵詞：	susceptible gene, HLA-C, SNP, NPC
相關次數：	點閱：123 下載：2
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鼻咽癌是一種盛行於中國東南方沿海地區的鱗狀上皮細胞癌。過去有許多研究指出特殊的遺傳因子造成人們容易受到EB病毒的侵襲與周圍環境因子（飲食習慣）的影響，經由這三種主要因子的交互作用進而慢慢發展成鼻咽癌。本研究主要探討遺傳因子與鼻咽癌的關係。先前的研究中，我們已發現一個位於HLA-C基因座附近的區域，它可能與鼻咽癌的易感受性有關。這段54 kb長的區域裡包含3個已知基因，分別是OTF3、SC1以及HCR基因。本研究分為兩大部分，第一部分是分析HLA-C基因座附近的鼻咽癌易感受性區域，其內的基因變異性與鼻咽癌的易感受性的相關。藉由Direct sequencing的技術，我們找到35個序列變異存在於鼻咽癌病患與正常健康人中。在我們收集到的鼻咽癌病患與正常健康人的genomic DNA檢體，利用PCR-SSP、SSOP、PCR-RFLP以及 real-time PCR等方法鑑別上述中的11個單一核甘酸多型性(SNP)。之後使用case-control association study統計分析序列變異與鼻咽癌易感受性的相關。統計的結果指出有兩個SNPs與鼻咽癌易感受性具有統計顯著相關 (p<0.05)。分別是HCR-SNP 21 (g.11648 C>T, rs3132539) (p=0.03, OR=0.49, T carrier mode)，SC1-SNP 8 (g.2335 G>A, rs2073721) (p=0.01, OR=2.19, G carrier mode)。其中SC1-SNP 8會造成胺基酸的改變 (V211M)，HCR-SNP 21則不會造成胺基酸的改變 (L597L)。第二部分是候選基因SC1的功能性分析，我們首先分析SC1-SNP 8在不同物種間的保守程度，發現G對偶基因普遍存在於不同的物種。此外我們也分析了目前既有的８株鼻咽癌細胞株，發現所有的鼻咽癌細胞株都帶有G/G的基因型。這樣的結果造成我們無法直接利用鼻咽癌細胞株來進行SC1-SNP8基因多型性的功能性分析，所以我們分別構築了SC1-SNP 8不同基因型的蛋白質表現載體 (pHA-SC1 variants/IRES2-EGFP)，它們將會表現SC1 V211 以及SC1 M211兩種不同蛋白質。之前的文獻指出SC1可能作為轉錄因子並且參與細胞週期後期的基因調控。藉由細胞週期的分析，我們得知在細胞週期的S phase早期，分別帶有不同SC1 (SC1V211M) 蛋白質的NIH/3T3細胞，其細胞週期的分佈會有所不同。另一方面，透過luciferase reporter gene assay，我們知道NLMP1 (EB病毒蛋白)會調控SC1基因的promoter活性。同時我們也知道SC1調控HCGIV-06基因 (一個會轉錄non-coding RNA的psuedogene) promoter活性的能力會因為V211M變異而有所不同。此外我們在共軛焦螢光顯微鏡下觀察到SC1 V211-EGFP fusion蛋白分佈在細胞核與細胞質中，SC1 M211-EGFP fusion蛋白則是主要分布在細胞質中。綜合上述結果，我們推測NLMP1可能會調控SC1表現量，而且SC1 V211M可能會改變細胞中的分佈，進而造成S phase早期的細胞週期分佈差異。除此之外，SC1 V221M 可能參與調控另一個NPC易感受基因 (HCGIV-06)。最後我們意外地發現兩個SC1基因的選擇性剪切產物，目前尚未有研究描述這兩種變異型的生物功能。鼻咽癌易感受性基因的發現將有助於我們了解鼻咽癌發生的病理機制。希望未來能將我們的結果應用在臨床診斷上，以達到早期預防的目標。

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma that is highly prevalent in southern Chinese, including people living in Taiwan. Numerous pieces of evidence suggest that genetic factors provide background susceptibility on which EBV infection and environmental factors may interact with each other and lead to the development of NPC. In a previous study, using HLA gene as linkage disequilibrium mapping tool and microsatellite marker for analysis, we have further identified a second NPC-susceptible locus localized within HLA-C region. Further study using microsatellite markers spanning 780 kb across the HLA-B and -C loci have narrowed down this NPC-susceptibility locus to within 54 kb. This study was divided into two major parts. Part I: To identify whether any DNA sequence variation is associated with genetic susceptibility to NPC within this 54 kb segment of putative NPC-susceptibility region. By DNA sequencing and genotyping study, we have first identified two genetic variations significantly associated with NPC among a number of single nucleotide polymorphisms (SNPs) found within this region. One is HCR-SNP 21 (g.11648 C>T, rs3132539) (p=0.03, OR=0.49, T carrier mode), another is SC1-SNP 8 (g.2335 G>A, rs2073721) (p=0.01, OR=2.19, G carrier mode). Part II: Functional study of SC1-SNP 8. SC1-SNP 8 caused an amino acid substitution at position 211 (V211M). Literature searches indicate that SC1 may play a role in cell cycle regulation. The genetic analysis of a number of NPC cell lines indicated that they all expressed G/G homozygote, and G allele is conserved in various mammalian species. To examine if this amino acid change may have any effect on the cell cycle distribution, wild type and variant expression vectors (pHA-SC1 variants/IRES2-EGFP) were transfected into mouse NIH/3T3 fibroblasts or NPC cell lines. In cell cycle distribution analysis, we found that the distinct cell cycle distribution of SC1 variants at early S phase of cell cycle. To investigate if the amino acid replacement may have any effect on the subcellular localization of protein expression, wild type and variants of SC1 and EGFP fusion protein-expressing plasmids were also constructed. The confocal microscope study revealed that SC1 V211-EGFP fusion protein was expressed in both nucleus and cytoplasm, but SC1 M211-EGFP fusion protein was predominantly expressed in cytoplasm. Moreover, the luciferase reporter assay indicated that NLMP1 may upregulate the promoter activity of SC1 gene. These data suggested that NLMP1 may regulate the SC1 gene expression at the transcription level, and the differential nucleocytoplasmic distribution of SC1 variants may cause the distinct cell cycle distribution at early S phase of cell cycle. Furthermore, we found that distinct inducing effects of SC1 variants on the promoter activity of HCGIV-06 (another putative NPC-susceptible gene). Finally, an unexpected we identified two novel alternative splice variants of SC1 from RT-PCR analysis of SC1 cDNA. The biological function of these two variants is currently unknown. The identification of NPC susceptible gene may shed light on how they may contribute to the development of NPC.

Abstract (Chinese)                                                 I
Abstract                                                               III
Acknowledgement　　　　　　　　　　        V
Content index　　　　　　　　　　　　　  VI　                                                          
Table index                                                           X
Figure index                                                        XII
Introduction                                                           1
Hypothesis                                                               5
Specific aims                                                             6
Materials and methods                                                                 7
Study participants                                                                        7
Human genomic DNA extraction method                                    7
Direct DNA sequencing                                                  7
Genotyping methods                                                    8
I. Genotyping by SSOP                                           8
II. Genotyping by PCR-SSP                                        8
III. Genotyping by PCR-RFLP                                      9
IV. Genotyping by melting curve analysis with hybridization probe    9
V. Genotyping by TaqMan probe                                   10
Cell line and Cell culture                                                11
I. HONE-1 culture condition                                     11
II. NPC Tw01, NPC Tw03, and NPC Tw04 culture condition            11
III. NIH-3T3 culture condition                                     12
RT-PCR (Reverse transcription-PCR)                                    12
Plasmid construction                                                 12
I. Construction of pMCS-Luc-enhancer like region vector            12
II. Construction of pHA-SC1/IRES2-EGFP expression vector         13
III. Construction of pHA-SC1-EGFP expression vector              14
IV. Construction of SC1 promoter vector                             14
SC1 cDNA probe cloning                                               14
Plasmid preparation                                                   15
Transient transfection                                                15
I. Calcium phosphate- mediated transfection                       15 
II. Lipofectamine transfection                                   15
Stable transfection                                                   16
Dual-Luciferase reporter assay                                          16
Site-directed mutagenesis                                               16
Preparation of whole cell lysate                                         17
Immunoblot                                                         17
Cell cycle synchronization                                             18
Flow cytometry for cell cycle analysis                                    18
Immunofluorescence analysis                                          19
Bioinformatic tools                                                                                                                                  19
Statistic methods                                                                                                                                      20
 
Results                                                                                                                                                     21
                                                         
Part I. Identification of Candidate SNPs in Putative Nasopharyngeal Carcinoma-susceptibility region    
                                
1. Direct sequencing of HCR gene                                                                                                           23                                       
2. Direct sequencing of SC1 gene and OTF3 gene                                                                                   23                             
3. Genotyping                                                              24                                                        
4. HCR-SNP 10 (g.6174 A>C, rs130067) is not associated with NPC risk in the
      Taiwanese population                                              24                                                                                                      
5. HCR-SNP 12 (g.7307 G>T, rs3094227) is not associated with NPC risk in the 
    Taiwanese population                                               25                                                                                                          
6. HCR-SNP 21 (g.11648 C>T, rs3132539) may play a protective role against
    NPC risk in the Taiwanese population                                  25                                
7. OTF3-SNP 1 (g.1306 G>T, rs2394882) is not associated with NPC risk in the
Taiwanese population                                          26                                                                           
8. OTF3-SNP 2 (g.1541 T>C, rs1061118) is not associated with NPC risk in the
Taiwanese population                                          26
9. OTF3-SNP 3 (g.1815 C>T, rs13409) is not associated with NPC risk in the
    Taiwanese population                                          27                                                                                                    
10. The association of SC1-SNP 4 (g.4513 A>T, rs1150766) and NPC risk 
    was still unknown                                                  28                                                         
11. SC1-SNP 5 (g.4438 C>T) variation may not exist in SC1 genomic sequence    28       
12. SC1-SNP 6 (g.4288 T>C, rs3132528) is not associated with NPC risk in the
    Taiwanese population                                          28                                           
13. SC1-SNP 7 (g.2361 C>A, rs2073722) is not associated with NPC risk in the
Taiwanese population                                          29                                                                                                     
14. SC1-SNP 8 (g.2335 G>A, rs2073721) is associated with NPC risk in the
Taiwanese population                                          30                                                        
15. Summary of genotyping results                                        30                                          

Part II. Functional analysis of candidate SNPs in Putative Nasopharyngeal Carcinoma-susceptibility Gene

1. The effects of ∆2 variation on enhancer-like region between SC1 and OTF3    33     
2.  Conservation of SC1V211 (GTG) across various species                   33   
3.  Characterize the SC1 expression in various NPC cell lines during cell growth   34     
4.  The effects of NLMP1 on the promoter activity of SC1                     35      
5.  The effects of SC1 variants on the promoter activity of HCGIV-06            36    
6.  Cell cycle distribution of NIH-3T3 transfected with SC1 variants expression vector    36  
7.  The subcellular localization of HA-SC1-EGFP variants fusion protein         37      
8.   Identification of two novel alternative splice variants of SC1                38     

Discussion                                                              39
The potential of HCR as NPC-susceptible gene                               39
Temporarily exclude OTF3 as NPC-susceptible gene                          40 
The potential of SC1 as NPC-susceptible gene                                40
SC1 expression in various NPC cell lines                                    41
The role of NLMP1 in regulation of SC1 transcription level                     41 
The effects of SC1 variants on promoter of HCGIV-06                         42
Distinct cell cycle distribution of SC1 variants                                42
The distinct nucleocytoplasmic distribution pattern of SC1 V211M               43
Novel alternative splice variants in SC1                                     43
Future work                                                           44

Reference                                                              45
Tables and Figures                                                       52
Appendixes                                                            108
自述                                                                       118
                                    

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