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研究生:林宣平
研究生(外文):Hsuan-Ping Lin
論文名稱:MYST4組蛋白乙醯酶對腫瘤細胞的影響
論文名稱(外文):The influence of histone acetyltransferase MYST4 on carcinomas
指導教授:毛翠蓮
指導教授(外文):Tsui-Lien Mao
口試委員:鄭永銘許晉銓陳彥榮
口試委員(外文):Yung-Ming JengJinn-Chyuan SheuYen-Rong Chen
口試日期:2013-07-10
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:病理學研究所
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:2013
畢業學年度:101
語文別:英文
論文頁數:54
中文關鍵詞:MYST4肝癌腫瘤移行組蛋白乙醯化酶
外文關鍵詞:MYST4hepatocellular carcinomamigrationhistone acetyltransferase (HAT)
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組蛋白乙醯化酶(HATs)在控制細胞生長和發育過程中扮演了關鍵的角色。然而一個已知的組蛋白乙醯化酶 MYST4與人類腫瘤發展的關係卻不明確。在我們先前的研究中,我們發現 MYST4在卵巢高惡性度漿液癌中有過量表現,且其過量表現與病患的較差預後有顯著相關。因此,我們想知道MYST4是否在其它腫瘤也有相同的現象。在這篇研究中,我們提供證據顯示MYST4與腫瘤的生長和進展有關。我們首先利用免疫染色發現MYST 4在肝癌及乳癌有高度表現,而且MYST4表現量跟肝癌患者存活率有顯著相關,這是第一個證據顯示MYST4可能參與肝細胞癌之進展。為了進一步了解 MYST4 基因在腫瘤細胞扮演的功能,我們利用定量逆轉錄聚合酶反應挑選出MYST4表現量高的腫瘤細胞株,包含A2780 卵巢癌細胞、SKBR3乳癌細胞及Huh7 肝癌細胞來進行敲減。細胞生長試驗及流式細胞儀細試驗的結果顯示MYST4有助於癌細胞之生長並且調控細胞週期。此外,在細胞移行試驗中,我們發現敲減MYST4 基因的細胞株其移行的能力大幅下降。這項發現指出MYST4促使腫瘤移行。我們進行微陣列試驗並發現多項基因之表現量在MYST4敲減下有負調節的現象,其中有幾個基因被證實參與腫瘤細胞之轉移。總歸而言,我們的研究顯示MYST4促使腫瘤細胞生長及移行。MYST4的高度表現會使腫瘤具有更侵犯的能力。

Histone acetyltransferases (HATs) play a critical role in the process of controlling cell growth and development. However, little is known about the relationship between MYST4, a known HAT, and human tumors. According to our previous studies, we found that MYST4 was overexpressed in ovarian high-grade serous carcinomas and patients with tumors overexpressing MYST4 had significantly worse survival. Therefore, we investigated whether MYST4 plays the same role in other cancers. Here we provide evidences that MYST4, may be involved in tumor cell growth and progression. By immunohistochemistry, we found that MYTS4 is highly expressesed in hepatocellular carcinomas (HCCs) and breast cancers than in normal tissues. Moreover, patients with HCCs overexpressing MYST4 had signigicantly worse survival. This is the first evidence suggesting that MYST4 may be involved in the progression of HCCs. In order to study the function of MYST4 in tumor cells, we used quantitative RT-PCR and selected several cancer cell lines including ovarian cancer cell line A2780, breast cancer cell line SKBR3 and hepatoma cell line Huh7 which expressed high levels of MYST4 and performed shRNA knockdown experiments. By cell proliferation assay and flow cytometry, we found that MYST4 enhanced cancer cell growth and regulated cell cycle progression. In addition, we observed that the migration distance was significantly decreased in MYST4 knockdown cell lines. This finding suggested that MYST4 promotes tumor migration. We performed microarray and found several target genes that were down-regulated by MYST4 knockdown, some may involved in cancer cell metastasis. Together, our study suggests that MYST4 promotes cancer cells growth and migration. Overexpression of MYST4 in cancer cells may induce tumors toward a more aggressive behavior.

口試委員會審定書 #
誌謝 II
中文摘要 III
ABSTRACT IV
CONTENTS VI
Chapter 1 Introduction 1
1.1 Ovarian cancer 1
1.2 Hepatocellular carcinoma 2
1.3 Histone 3
1.4 Histone acetyltransferases 3
1.5 The MYST family of HATs 4
1.6 MYST4 5
1.7 MYST family and carcinoma 6
1.7.1 Tip60 6
1.7.2 MOF 6
1.7.3 HBO1 7
1.7.4 MOZ/MORF 8
1.8 MYST4 and developmental disorders 9
1.9 Previous study of MYST4 in ovarian carcinomas 9
1.10 Aims of this study 10
Chapter 2 Materials and methods 11
2.1 Immunohistochemical stain 11
2.2 Cell culture 11
2.3 RNA interference 12
2.4 RNA isolation 12
2.5 Quantitative real-time-PCR (qRT-PCR) 12
2.6 Cell migration assay 13
2.7 Cell proliferation assay 13
2.8 Flow cytometry 13
2.9 Microarray 14
2.9 Statistical analysis 14
Chapter 3 Results 16
3.1 MYST4 was overexpressed in HCC and breast cancers 16
3.2 Correlation of MYST4 expression and clinical parameters in HCC 16
3.3 MYST4 was highly expressed in liver cancer cell lines 16
3.4 Knockdown of MYST4 reduced human ovarian, breast and liver cancer cell proliferation 17
3.5 Knockdown of MYST4 inhibited cell cycle progression 18
3.6 Knockdown of MYST4 suppressed cell migration 18
3.7 Analysis of downstream genes selected from MYST4 knockdown microarray 18
Chapter 4 Discussion 21
Chapter 5 Figures and Tables 27
Figure 1. Immunohistochemical stain of MYST4 in HCC specimens and normal liver tissues 27
Figure 2. Kaplan-Meir analysis showed higher MYST4 expression correlated with poorer survival in HCC patients 29
Figure 3. RT-PCR comparing the expression level of MYST4 among different types of cancer cell line and efficiency of MYST4 knockdown 31
Figure 4. Effect of MYST4 on the proliferation of human cancer cell line 33
Figure 5. Cell cycle distribution in MYST4 knockdown cell lines 35
Figure 6. Knockdown of MYST4 suppresses cell migration 39
Figure 7. Expression of genes selected from micro-array in HCCs 43
Table 1. Univariate analysis of MYST4 expression and clinicopathologic parameters in patients with HCC………………………………………….45
Table 2. The shRNA sequences for RNA interference 45
Table 3. The sequences of primers for qRT-PCR 46
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