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研究生：	鄒仁蕙 Tsou, Jen-Hui
論文名稱：	探討Aurora-C (AURKC)基因在腫瘤形成過程中之角色與轉錄調控機制 The role and transcriptional regulation of Aurora-C (AURKC) in tumorigenesis
指導教授：	洪良宜 Hung, Liang-Yi
學位類別：	博士 Doctor
系所名稱：	生物科學與科技學院 - 生物資訊與訊息傳遞研究所 Insitute of Bioinformatics and Biosignal Transduction
論文出版年：	2011
畢業學年度：	100
語文別：	英文
論文頁數：	105
中文關鍵詞：	AURKC 、PLZF 、子宮頸癌、大腸直腸癌、轉型
外文關鍵詞：	AURKC, PLZF, cervical cancer, colorectal cancer, transformation
相關次數：	點閱：120 下載：1
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Aurora 激酶家族屬於serine/threonine 蛋白激酶，在哺乳動物中存在有AURKA, -B 及 -C 三個成員。AURKA 和-B 在許多組織中均有表現，對於調控細胞週期扮演不可或缺的角色。先前研究指出過量表現的AURKA 和-B 會誘導centrosomes amplification、chromosom instability 及不正常的cytokinesis，最終可能導致腫瘤的形成。AURKC 主要侷限於睪丸組織中表現，目前對於其功能了解很少。近來有許多報告指出，AURKC在人類大腸直腸癌，甲狀腺癌和數種癌細胞株中被偵測到有表現的情形。然而，對於為何在癌細胞中AURKC 會表現，以及AURKC 在癌細胞中的作用，目前仍不清楚。在本論文，我們發現AURKC 的確會表現於許多癌細胞株。將AURKC 過量表現於HeLa 及A549 細胞，會增強癌細胞proliferation，transformation 及migration 的能力。於xenograft 動物模式中也發現，大量表現的AURKC會增加腫瘤的大小及重量。更重要的，AURKC 的激酶活性對於這些癌化的特質是必須的。分析人類癌組織檢體，也可發現AURKC 的表現，且其表現與子宮頸癌癌症形成的進程有關，與大腸直腸癌的N status 和MAC stage 亦有高度相關。此外，我們發現，在精子生合成過程中扮演重要角色的PLZF 與Aurkc 的表現呈現相反的情形。進一步分析人類子宮頸癌及大腸直腸癌組織，也證實PLZF 與AURKC mRNA 的表現呈現相反的趨勢。利用報導基因實驗分析，HA-PLZF 確實可專一性地抑制AURKC 基因的表現。染色質免疫沉澱分析進一步證實HA-PLZF 的確會結合在AURKC 啟動子區域。免疫螢光染色的結果顯示，過量表現的AURKC-GFP 會位於有絲分裂染色體的中心體區域，且導致細胞內原本AURKB 蛋白的表現量和激酶活性減少。有趣的是，在轉移性較強的SW620 細胞中，內生性的AURKC 表現量相較於SW480 細胞比較高的。臨床檢體的分析也顯示，AURKB 和AURKC 在大腸直腸癌中的表現是呈現相反的模式。這些結果顯示，AURKC 的確在人類癌細胞中會有過量表現，而PLZF 可能是調控其表現的轉錄因子。

Aurora is a family of serine/threonine protein kinases. There are three members in mammals: AURKA, -B, and -C. AURKA and -B are expressed in many tissues, and play essential roles in regulating many important events during cell-cycle progression. Previous studies indicated that the overexpression of AURKA and -B can induce centrosome amplification, chromosome instability, and abnormal cytokinesis, and ultimately lead to tumor formation. AURKC has restricted expression in the testes, and less is known about its function. Recently, many reports indicated that AURKC overexpression was detected in human colorectal cancers, thyroid carcinoma, and several cancer cell lines. However, the reason for and the effect of AURKC being overexpressed in cancer cells are unclear. In this study, we found that AURKC is actually expressed in numerous cancer cell lines. Elevated expression of AURKC in HeLa and A549 cells increased the proliferation, transformation, and migratory abilities of cancer cells. In an animal xenograft model, AURKC overexpression enhanced the tumor size and weight. Interestingly, kinase activity is required for these tumorigenic properties of AURKC. Analysis of human cancer specimens showed that the increased expression of AURKC accompanied the progression of human cervical cancer, and was highly correlated with the N status and MAC stage of human colorectal cancer. In mouse testes, PLZF, which plays a crucial role in spermatogenesis, showed a reciprocal expression pattern with Aurkc. In an analysis of human cervical and colorectal cancer tissues, data indicated that expression levels of PLZF and AURKC mRNA displayed opposite patterns. Results of a reporter assay indicated that HA-PLZF specifically inhibited the expression of AURKC, but not AURKA or AURKB. A chromatin immunoprecipitation assay further showed that HA-PLZF can be recruited to the AURKC promoter region. In an immunofluorescence assay, AURKC-GFP overexpression was localized to centromeric regions of mitotic chromosomes and resulted in decreased protein expression levels and kinase activity of endogenous AURKB in HeLa cells. Interestingly, the endogenous protein level of AURKC was higher in more-metastatic SW620 cells than in SW480 cells. Analysis of clinical cancer specimens also showed that expression levels of AURKB and AURKC were in an inverse pattern in colon carcinoma. Taken together, our results indicate that AURKC is indeed overexpressed in human cancer cells, and AURKC expression may be due to loss of inhibitory regulation by PLZF.

Abstract in Chinese I
Abstract II
Acknowledgment III
Table of Contents IV
List of Figures VIII
List of Tables IX
List of Appendices X
Abbreviations XII
Chapter 1: Introduction 1
1. The cell cycle 1
2. Introduction of the M phase 1
3. Progression of mitosis is controlled by several protein kinases 2
4. Aurora kinases 2
5. Localization and function of Aurora kinases 3
5.1. AURKA 3
5.2. AURKB 3
5.3. AURKC 3
6. Expression of Aurora kinases 4
6.1. AURKA 4
6.2. AURKB 4
6.3. AURKC 5
7. Aurora kinases and cancer 5
7.1. AURKA 5
7.2. AURKB 6
7.3. AURKC 6
8. Promyelocytic leukemia zinc-finger (PLZF) 6
9. PLZF represses target gene expression 7
10. Physiological role of the PLZF 8
11. Research aims 9
Chapter 2 : Materials and Methods 10
I. Materials 10
1.Chemical compounds 10
2. Primers used in this study 14
3. Antibodies used in this study 15
Ⅱ. Methods 16
1. Complementary (c)DNA expression array 16
2. Preparation of cell lysates and Western blot analysis 16
3. Sample of clinical specimens 17
4. Immunohistochemical staining 17
5. Statistical analysis 18
6. Cell counting assay 18
7. Colony formation assay 18
8. Anchorage-independent growth assay 19
9. Migration assay 19
10. Xenograft analysis 19
11. In situ cell death assay 20
12. Flow cytometry analysis 20
13. Fractionation of mouse testis 21
14. Cell culture and transfection 21
15. Promoter construct and reporter assay 21
16. Chromatin immunoprecipitation (ChIP) and sequential ChIP assay 22
17. Quantitative polymerase chain reaction (Q-PCR) and reverse-transcription (RT)-PCR 23
18. Sodium bisulfite modification of genomic DNA and methylation-specific PCR 23
19. Immunofluorescence assay 23
Chapter 3: Results 25
A. AURKC is expressed in many cancer cell lines and cancer tissues 25
1. Overexpression of AURKC mRNA is observed in many cancer cell lines and human cancer tissues 25
2. The AURKC protein is overexpressed in human cervical and
colorectal cancer tissues 25
3. Concomitant AURKC and normal-dysplasia/carcinoma in situ
(CIS)-squamous cell carcinoma (SCC) sequence expressions in primary cervical tissues 26
4. Expression of AURKC is positively correlated with lymph node metastasis (N status) and modified Astler-Coller (MAC) staging in human colorectal cancer 27
B. AURKC overexpression enhances the transformation and tumorigenic activities of cancer cells 27
1. Augmented expression and increased kinase activity of AURKC enhance proliferative and transformation activities and migratory ability of cancer cells 27
2. AURKC enhances tumor growth in an animal xenograft model 28
3. AURKC kinase activity enhances phosphorylation levels of
AKT/Ser-473 and improves the cell survival ability 29
C. AURKC expression is repressed by the tumor suppressor, PLZF 29
1. Plzf has an opposite expression pattern to Aurkc in
spermatogenesis 29
2. PLZF negatively regulates Aurkc gene expression 30
3. PLZF is recruited to the AURKC promoter and represses its gene expression 31
4. Opposite expression patterns of PLZF and AURKC in cancer
tissues paired with normal tissues 31
5. PLZF specifically represses AURKC expression 32
6. The repressive effect of PLZF on AURKC expression is not
through an interaction with nuclear co-repressor factors 33
7. AURKC expression is not regulated by an epigenetic effect 33
D. AURKC overexpression decreases the expression of AURKB in
cancer cells 34
1. AURKC overexpression displaces the centromeric localization of AURKB and decreases the AURKB expression level in cancer cells 34
2. The correlation between AURKB and AURKC does not differ in the CIS-SCC sequence in primary cervical tissues, but shows an inverse pattern in colon carcinoma 35
Chapter 4: Discussion 37
A. AURKC has oncogenic activity and may be able to serve as a potential target for cancer therapy 37
B. AURKC kinase activity is important for the survival and tumorigenecity of cancer cells 38
C. The possible mechanism of PLZF in repressing AURKC expression 40
D. The presumable factors in activating AURKC expression 42
E. The effect of AURKC overexpression on the expression of AURKB and activation of the SAC 43
Chapter 5: Conclusions 45
References 46
Figures 52
Tables 80
Appendices 87
Publications 103
Curriculum vitae 104
                                    

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