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系統識別號 U0026-0108201115012900
論文名稱(中文) ZNF322A過度表現導致p53和cyclin D1轉錄調控變異與肺癌相關性研究
論文名稱(英文) ZNF322A overexpression leads to transcriptional deregulation of p53 and cyclin D1 in lung cancer
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 99
學期 2
出版年 100
研究生(中文) 陳湘婷
研究生(英文) Hsiang-Ting Chen
學號 s26981092
學位類別 碩士
語文別 英文
論文頁數 84頁
口試委員 指導教授-王憶卿
口試委員-洪建中
口試委員-陳炳焜
中文關鍵字 致癌基因  細胞增生  肺癌 
英文關鍵字 ZNF322A  oncogene  CCND1  p53  cell proliferation  AP-1  lung cancer 
學科別分類
中文摘要 研究背景: 本實驗室在先前的研究中使用比較基因體學挑選出具有研究潛力的候選致癌基因- ZNF322A。利用real-time PCR及chromogenic in situ hybridization (CISH) 的實驗技術,證實ZNF322A基因無論在國內外的肺癌病人,染色體結構擴增的頻率皆大於50%。ZNF322A位於染色體6p22.1,屬於zinc-finger transcription factor family中的一員。前人研究發現,ZNF322A過度表現會增加SRE (serum response element)及AP-1 (activator protein 1) binding elements的轉錄活性。然而,截至目前為止仍沒有ZNF322A變異跟腫瘤形成相關的文獻被報導。
研究目的: 藉由人類肺癌細胞、動物及臨床模式,探討ZNF322A致癌機制為何。
研究結果: 本研究在100位台灣肺癌病人中發現75位 (75%) mRNA有過度表現,且ZNF322A mRNA過度表現和鱗狀上皮肺癌 (squamous cell carcinoma) 相關 (P=0.038)。將病人的腫瘤組織以免疫染色 (immunohistochemistry) 分析其ZNF322A蛋白表現,74% (74/100) 呈現過度表現,也同樣看到和鱗狀上皮肺癌相關 (P=0.011);另外,在74位美國肺癌病人中有54位 (72.9%) 蛋白有過度表現。本研究亦發現ZNF322A蛋白的過度表現可當作東西方女性病人的預後指標 (分別為P=0.040及P=0.037)。接著,我們在細胞模式將ZNF322A基因overexpression,會促使細胞週期從G1期進入S期而加速細胞增生(cell proliferation) 及細胞群落形成的能力 (colony formation);若knockdown ZNF322A基因則會看到相反的影響。進一步我們在動物實驗模式中將ZNF322A基因overexpression,發現會促使腫瘤的生長速率,knockdown則會看到相反的影響。除了影響腫瘤生長速率外,我們進一步檢測ZNF322A是否會影響癌細胞爬行(migration)及侵略(invasion) 的能力,實驗結果發現ZNF322A基因 overexpression會促進肺癌細胞株爬行及侵略轉移力。
由於ZNF322A為一個轉錄因子,所以接下來進行luciferase activity檢測是否從轉錄層次調控可能下游基因Cyclin D1 (CCND1) 及p53的轉錄活性。實驗結果發現ZNF322A會從轉錄層次正向調控CCND1而負向調控p53轉錄活性。我們進一步利用chromatin immunoprecipitation (ChIP),發現 ZNF322A能與CCND1及p53 啟動子含有AP-1 sites的區域結合。此外,若將肺癌細胞的 ZNF322A 基因overexpression,會增加CCND1 而且降低p53 mRNA及蛋白的表現量,knockdown則會看到相反的影響。接著,我們檢測CCND1及p53染色質結構,發現若將ZNF322A knockdown,會減少H3K9K14 acetylation 修飾作用,使CCND1染色質呈現緊密的狀態而不利於基因的轉錄;反之,則會使p53結構呈現疏鬆的狀態。為了揭示更多ZNF322A的轉錄目標基因,本研究以表現圖譜 (expression array) 與路徑分析 (pathway analyses),發現會受ZNF322A所調控的基因中,有17%的基因參與調控細胞生長相關的路徑;除此之外,也發現和調控細胞爬行及轉移相關的基因。顯示ZNF322A不僅會影響腫瘤細胞的生長能力,也有影響細胞爬行及轉移的潛力。
結論: 本篇研究是首篇提出ZNF322A由於基因體結構擴增而導致過度表現,進而透過異常調節CCND1及p53基因而促使腫瘤形成及病人較差的預後。未來,更多ZNF322A的轉錄目標基因與肺癌形成與進展機制,將由人類肺癌細胞、動物及臨床模式驗證。
英文摘要 Background: ZNF322A was revealed as a potential oncogene in lung cancer patients using an array-comparative genomic hybridization in our previous study. Real-time PCR and chromogenic in situ hybridization assays confirmed that DNA copy number amplification of ZNF322A locus occurred in both Asian and Caucasian lung cancer patients. ZNF322A was found to encode a transcription factor increasing the transcriptional activity of genes containing SRE (serum response element) or AP-1 (activator protein 1) element.
Purpose: Since the role of ZNF322A has never been reported in human cancer, the current study aimed to investigate the oncogenic mechanisms of ZNF322A in lung cancer cell, animal and clinical models.
Results: ZNF322A mRNA was overexpressed in 75% (75/100) of tumors and significantly correlated with squamous cell carcinoma in Asian patients. The frequency of ZNF322A protein overexpression was 74% (74/100) in Asian and 72.9% (54/74) in Caucasian lung cancer patients using immunohistochemistry. Female patients with overexpressed ZNF322A protein had poor overall survival both in Asian (P=0.040) and Caucasian (P=0.037). We further studied the oncogenic role of ZNF322A in cell model. Overexpression of ZNF322A enhanced cell growth in H460 lung cancer cell and Beas2B normal lung epithelial cell. Conversely, knockdown of ZNF322A decreased cell proliferation and anchorage-independent growth in A549 lung cancer cell. Furthermore, we performed tumor growth assay in vivo to confirm that ZNF322A markedly accelerated tumor growth. In addition, the effects of ZNF322A on cell migration and invasion were examined. The results showed that ZNF322A overexpression could accelerate the migration and invasion ability of lung cancer cells.
We investigated whether ZNF322A may modulate expression of genes with SRE or AP-1 sites, such as CCND1 and p53. Overexpresson of ZNF322A positively regulated CCND1 mRNA and protein expressions but negatively regulated p53 mRNA and protein expressions in H460 cells. Knockdown of ZNF322A showed the reverse effects in A549 cells. Using luciferase activity assay, we found that CCND1 and p53 were transcriptionally regulated through ZNF322A in A549 and H460 cell lines. Chromatin-immunoprecipitation PCR showed that ZNF322A bound to the promoter region including AP-1 sites of CCND1 and p53 genes. Knockdown of ZNF322A resulted in a repressed chromatin structure of CCND1 promoter evident by loss of H3K9K14 acetylation. In contrast, p53 promoter showed an open chromatin structure. To reveal more transcriptional target genes of ZNF322A, we performed expression array analyses. The pathway analyses indicated that 17% of the ZNF322A-regulated genes were involved in cell-growth control pathways. In addition, some genes involved in cell migration control pathways were found. The data implied that ZNF322A not only regulates tumor growth but also has effects on regulation cancer cell migration and metastasis.
Conclusion: Our results provide first evidence that amplification and overexpression of ZNF322A contribute to lung tumorigenesis and poor prognosis. These effects are partly mediated through deregulation of cell-cycle control genes such as CCND1 and p53. More transcriptional target genes of ZNF322A revealed by array analyses will be further validated.
論文目次 Introduction 1
I. Lung cancer
(a) Clinical importance 1
(b) Molecular alterations 1
(b) Our previous array-comparative genomic hybridization
(array-CGH) results 2
II. ZNF322A in previous study
(a) Identification and general structure of ZNF322A gene and protein 3
(b) ZNF322A is ubiquitously expressed in adult tissues and
different embryo stages 4
(c) ZNF322A functions as a potential transcriptional activator 5
(d) ZNF322A involves in MAPK pathway through an AP-1 dependent manner 6
III. Transcriptional regulation of p53 and cyclin D1 genes
(a) Activator protein 1 (AP-1) 7
(b) Regulation of p53 and cyclin D1 genes 8
Study basis and specific aims 10
Materials and Methods 11
I. Study population 11
II. RNA extraction and quantitative reverse-transcriptase PCR
(RT-qPCR) assays 12
III. Immunohistochemistry (IHC) assay 12
IV. Cell culture 13
V. Plasmid, RNAi and transfection 14
VI. Analysis of cell proliferation 14
VII. Colony formation 14
VIII. Flow cytometry 15
IX. Transwell migration and invasion assays 15
X. Western blot 16
XI. Dual luciferase assay 17
XII. Chromatin immunoprecipitation (ChIP)-PCR assay
and qPCR assays 17
XIII. Immunoprecipitation (IP) and Western blot 18
XIV. Cancer growth assay in animal study 18
XV. Expression array analysis 19
XVI. Statistical analysis 20
Results 21
I. In clinical model:
(a) ZNF322A protein expression level significantly correlates
with mRNA expression level and is frequently overexpressed in squamous cell carcinoma in Asian lung cancer patients 21
(b) Patients with overexpressed ZNF322A protein have poor
overall survival in Caucasian lung cancer patients 22
(c) ZNF322A and CCND1 coordinately overexpress in Asian lung cancer patients 22
II. In cell model:
(a) ZNF322A expression level is higher in lung cancer cell lines than normal lung cells 23
(b) Overexpressed ZNF322A promotes cell proliferation and colony formation in lung cells 23
(c) ZNF322A binds to the region containing AP-1 sites and regulates CCND1 and p53 transcription 24
(d) ZNF322A interacts with c-Jun and corporately binds to the region containing AP-1 sites 25
(e) ZNF322A changes the chromatin modifications of CCND1 and p53 promoters 26
(f) Other putative transcriptional targets of ZNF322A 26
(g) Overexpressed ZNF322A promotes cell migration in
lung cells 28
III. In animal model:
(a) ZNF322A overexpression accelerates tumor growth
in vivo 28
(b) ZNF322A knockdown inhibits tumor growth in vivo 29
Discussion 31
References 35
Tables 42
Figures 56
Appendix 78
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